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_734_Библиотеки_им_академика_М_И_Перельмана.pdf
16 Pancreatic Ductal Adenocarcinoma
283
developed grade 3 or 4 adverse effects compared to 52.9% of patients on the gemcitabine arm [40].
The development of nanoparticle albumin-bound (nab)-paclitaxel has signicantly changed its efcacy in combination therapy. Nab-paclitaxel was developed to
make paclitaxel more soluble. Additionally, murine models show that nab-paclitaxel
depletes tumor desmoplastic stroma. Nab-paclitaxel, when used in combination
with gemcitabine, triples the tumor tissue drug concentration of gemcitabine [41,
42]. In the Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), 861
patients with advanced PDAC and good performance status were randomized to
gemcitabine and nab-paclitaxel or gemcitabine alone. Gemcitabine plus nabpaclitaxel showed improved OS (8.5 months vs. 6.7 months p < 0.001), longer
progression- free survival (5.5 months vs. 3.7 months, p < 0.001), and higher
response rates (23% vs. 7%, p<0.001) [28]. Like gemcitabine alone, it appears that
the toxicity prole of gemcitabine plus nab-paclitaxel therapy is better than that
seen in the FOLFIRINOX study. Gemcitabine plus nab-paclitaxel is now another
option for rst-line chemotherapy for patients with pancreatic cancer.
Chemoradiation
Locoregional recurrence is common even after R0 resection, occurring in up to
20–60% patients. Chemoradiation was initially employed in the adjuvant setting to
address this high risk of locoregional recurrence [43–46]. In a cohort of 531 patients
who developed recurrence after pancreatectomy, Groot etal. found that 23.7% of
patients developed isolated local recurrence while an additional 18.5% of patients
had both local and distant sites of recurrence [47]. Similarly, a secondary analysis
of the ESPAC-4 trial by Jones etal. showed that 32% of patients who develop recurrence after pancreatectomy develop local-only recurrence [48]. This group of
patients would theoretically stand to benet from chemoradiation as an additional
modality of local control for PDAC.Kalser etal. [49] showed that adjuvant chemoradiation improves survival even after R0 resection with a median survival of
20months vs. 11months in the observation arm. This study was underpowered but
led to increased adoption of chemoradiation as part of the standard of care after
pancreatic cancer resection in the United States [50]. Also in the adjuvant setting, a
propensity-score-matched study with 1386 patients showed 33% improved overall
survival (p<0.001) with the addition of chemoradiation as compared to resection
alone [51]. European studies have not reproduced these results and have instead
found mixed survival outcomes with the addition of chemoradiation, ranging from
statistically signicant but small benet [52] to reduced survival among patients
receiving chemoradiation in the ESPAC-1 trial [53]. This has fueled further debate
on the use of adjuvant chemoradiation, and it has therefore not been universally
adopted. There is consensus, however, that a subset of resected patients may benet
from chemoradiation if carefully selected for high risk of developing locoregional
disease recurrence [54].
284
R. J. Bello and C. N. Clarke
Neoadjuvant Trials
Chemotherapy
It is now widely accepted that patients with borderline resectable and locally
advanced PDAC who are surgical candidates should undergo neoadjuvant chemotherapy prior to pancreatectomy. Precedence is given to induction chemotherapy for
these patients, as many reports have demonstrated an increased proportion of borderline resectable patients that will undergo resection with margin-negative resection and consequent improved outcomes after neoadjuvant chemotherapy. In a
series of 18 patients with borderline resectable PDAC by Christians et al. [55],
patients underwent preoperative FOLFIRINOX (5-FU, oxaliplatin, irinotecan, and
leucovorin) followed by chemoradiation with gemcitabine or capecitabine as radiosensitizing agents. Restaging scans prior to chemoradiation showed that none of
these patients progressed while on FOLFIRINOX and 12 (67%) of them proceeded
to resection, all achieving R0 resection. Ten (83%) of these patients required portal
vein resection and reconstruction. All tumors had more than 50% nonviable tumor
on nal pathology, and only two (17%) patients had positive nodes. This study did
not report on median survival for the pancreatectomy group because it has not been
reached yet. With 22months of median follow-up, however, 7 (58%) patients were
still alive, and 5 (42%) patients had no evidence of disease. Median survival for the
patients who did not undergo resection due to progression of disease was
12.5months.
There is more room for debate regarding neoadjuvant chemotherapy for patients
with resectable PDAC who would be otherwise eligible for upfront resection. The
SWOG trial by Sohal etal. randomized 147 patients with localized PDAC to receive
either perioperative modied FOLFIRINOX or perioperative Gemcitabine/nabPaclitaxel. Of the patients enrolled in the study, 72% underwent resection and 85%
had R0 resection, demonstrating the feasibility of this treatment approach [56].
They report an 85% completion rate of neoadjuvant chemotherapy in both arms
[56], which is substantially higher than the approximately 54% of patients who
complete adjuvant therapies after pancreatectomy [57]. The recently published
NORPACT-1 trial was a phase 2, randomized, multicenter clinical trial comparing
4cycles of neoadjuvant FOLFIRINOX to upfront surgery, both followed by adjuvant chemotherapy. This study showed signicantly lower survival at 18months in
the intention-to-treat analysis for patients in the neoadjuvant chemotherapy group
(60% vs 73%, p = 0.032) despite having signicantly higher proportions for R0
resection and N0 disease. Per the trial authors, these results were inconclusive as a
phase 2 trial. There were signicant challenges in implementing neoadjuvant
FOLFIRINOX in the trial, as 40% of patients in the neoadjuvant chemotherapy
group did not complete all 4cycles of therapy. Moreover, the proportion of patients
in the neoadjuvant chemotherapy group who received modied FOLFIRINOX as
adjuvant treatment was lower than in the upfront surgery group (25% vs 43%) [58].
At the author’s institution, we favor neoadjuvant chemotherapy for patients with
16 Pancreatic Ductal Adenocarcinoma
285
resectable PDAC as a mechanism to administer systemic treatment prior to pancreatectomy for what is primarily a systemic disease. We believe this approach benets
patients by increasing the proportion of patients who complete all intended therapies, as evidenced in the SWOG trial, as well as by selecting patients who will
develop early metastatic disease or recurrence, sparing them from the morbidity of
a pancreatectomy that would have been unlikely to benet them. It is necessary to
ensure early surgical involvement in treatment decision-making and close follow-up
throughout receipt of neoadjuvant therapies to identify and treat any modiable
treatment toxicities and appropriately obtain restaging scans at regular intervals
before pancreatectomy.
Chemoradiation
There is emerging evidence for the role of chemoradiation in the neoadjuvant setting, especially for patients with borderline resectable and locally advanced disease.
The objective of chemoradiation for these patients, in addition to neoadjuvant chemotherapy, is to downsize the tumor, increase the potential for R0 resection, and
decrease regional lymph node positivity.
Neoadjuvant chemoradiation has been demonstrated in some reports to be associated with improved R0 resection rates as well as improved survival for patients
with borderline resectable and locally advanced PDAC [26, 34, 59–61]. Recent
studies using FOLFIRINOX and chemoradiation have shown margin-negative rates
between 80% and 100% [34, 55]. Neoadjuvant chemoradiation is associated with
higher rates of negative regional lymph nodes: 73% with chemoradiation compared
to 14% in upfront surgery patients (p<0.001) [59]. Conventional chemoradiation
has not been shown to signicantly reduce tumor size, but when used in combination with contemporary neoadjuvant chemotherapy, approximately 33% of patients
with unresectable, locally advanced pancreatic cancer can be downstaged to resectable [62–64]. The PREOPANC study, which failed to demonstrate any signicant
benet from neoadjuvant chemoradiation alone in patients undergoing pancreatectomy and adjuvant gemcitabine, recently published long-term results favoring neoadjuvant chemoradiation. For the 119 patients randomized to neoadjuvant
chemotherapy, 5-year overall survival was signicantly higher than that with upfront
surgery (20.5% vs 6.5%, p=0.025) and this benet was consistent for both resectable and borderline resectable PDAC [65].
Treatment of PDAC with shorter courses of radiation is possible with stereotactic
body radiation therapy (SBRT). SBRT delivers higher doses of radiation in fewer
fractions, reducing the total length of treatment which is an attractive option in the
neoadjuvant setting. There are statistically comparable results for SBRT and conventional fractionation in terms of outcomes in local control and R0 resection
[66–68]. In a study by Rajagopalan etal., 12 patients with either borderline resectable or locally advanced pancreatic cancer received between 24 and 36Gy of neoadjuvant radiation therapy. This was fractionated in between 1 and 3 doses with a
286
R. J. Bello and C. N. Clarke
median of 3.3months before surgery. Notably, 11 of these patients had received
induction chemotherapy. They reported that R0 resection was achieved in 11 (92%)
patients. Furthermore, 3 patients (25%) had complete pathologic response and 2
(17%) had <10% viable tumor in the specimen. Overall survival was 92% at 1year
and 51% at 3years. Progression-free survival was a median of 27.4months [68]. In
another study by Chuong etal., 73 patients received 35Gy to the tumor–vascular
interface and 25Gy to the rest of the tumor over ve fractions of radiation therapy.
Of these, 32 patients (44%) underwent resection with 97% R0 resection and local
control rate of 81%. Median overall survival for this cohort was 19.3 months.
However, only 20 of these patients (65%) had negative nodes on pathology, a lower
node “sterilization” rate than that reported in conventional radiation cohorts [66].
The recent Alliance A021501 trial by Katz etal. randomized patients with borderline resectable PDAC to receive neoadjuvant modied FOLFIRINOX alone or neoadjuvant modied FOLFIRINOX followed by SBRT or hypofractionated
image-guided radiotherapy. At the rst interim analysis, the radiation therapy arm
was closed early due to lower survival rates compared to the neoadjuvant chemotherapy alone arm [69]. It is unclear whether this lack of effectiveness will change
with long-term follow-up like the PREOPANC study or if there is a true lower
effectiveness in SBRT for this patient population. Another concern for SBRT is
development of delayed complications, such as postoperative wound issues and vascular injury [66, 68]. We look forward to results from current clinical trials to add
evidence on ideal fractionation of radiation therapy in the neoadjuvant setting for
pancreatic cancer.
Pancreatectomy
After completing all intended neoadjuvant therapy, repeat high-resolution CT imaging with a pancreas protocol and serum biomarkers should be obtained prior to
pancreatectomy. This allows for assessment of response, and updated surgical planning particularly as it relates to anticipated need for vascular resection and reconstruction. Outcomes are signicantly better at high-volume centers for pancreatic
resection, in part due to surgeon expertise and also due to institutional-level ability
to rescue patients from serious complications and death after developing complications [70]. Timing is also an important determinant of perioperative risk. Since the
median age for new pancreatic cancer patients is 70years [24], pancreatectomy is
most often performed in older adults who are at higher risk for deconditioning with
chemotherapy and radiation therapy. This highlights the importance of multidisciplinary management of pancreatic cancer patients including an evaluation for surgical candidacy at each stage of neoadjuvant therapy. This should happen at least at
the time of diagnosis, at the end of neoadjuvant chemotherapy and, if applicable, at
the end of chemoradiation, making it possible to act on any reversible causes of
morbidity which could turn a potentially resectable patient into one that is not a
surgical candidate anymore. At our institution, we base decisions on surgical
16 Pancreatic Ductal Adenocarcinoma
287
resectability for localized pancreatic cancer at each stage of multimodal neoadjuvant therapy, evaluating maintenance of good performance status, improved or stable ndings on CT scan, and normalization or improvement of CA19-9 when
informative [71]. There has been a move toward implementing enhanced recovery
after surgery (ERAS) protocols at large volume centers including prehabilitation
interventions before pancreatectomy to optimize patient nutritional status, physical
tness, and education prior to resection. Guidelines for patients undergoing Whipple
procedure are available from the Enhanced Recovery After Surgery (ERAS®)
Society and aim at reducing deconditioning preoperatively and decreasing postoperative complications [72]. There has been a positive experience with ERAS protocols for pancreatic resection patients. Implementation of these has been associated
with shorter hospital length of stay and decreased postoperative complications without a negative impact on oncologic outcomes [73, 74].
Specically for patients with borderline resectable pancreatic cancer, there
should be special attention to the vascular anatomy and presence of encasement of
vessels. This is key to maintaining low morbidity and mortality, as well as good
oncologic outcomes. Any unanticipated requirement of vascular resection or reconstruction could result in a major vascular injury and major blood loss. There is high
correlation between high-quality preoperative CT scans and intraoperative ndings,
allowing detailed operative plans to be made in advance, including need for vascular
resection and reconstruction. Prior to laparotomy, diagnostic laparoscopy should be
performed, especially in patients with borderline resectable PDAC as up to 13%
will have occult metastatic disease at the time of the operation [60, 62].
Venous Resection andReconstruction
There has been increasing experience with resecting and reconstructing the PV and
SMV in patients with borderline resectable PDAC and venous involvement. Patients
with abutment, encasement, and even occlusion of the PV-SMV conuence may
still be eligible for resection if there is adequate inow and outow targets for
reconstruction. R0 resection is still anticipated in these patients. Resection of tumors
invading the PV-SMV conuence must be preceded by careful planning due to substantial variation in the anatomy of rst order jejunal and ileal branches, as well as
variation in drainage of the inferior mesenteric vein (IMV). In general, if the IMV
drains into the splenic vein, the splenic vein can be ligated as the IMV will provide
enough drainage into the systemic venous circulation for the spleen. Otherwise, if
the IMV drains into the SMV or at the SMV-PV conuence, ligation of the splenic
vein without reconstruction can lead to sinistral venous hypertension by relying
only on the short gastric veins to drain the spleen. Splenorenal shunting is therefore
recommended in these cases [75]. Temporary mesocaval shunts can aid in portal
dissection for patients with PV occlusion and facilitate exposure of the SMA and
root of the mesentery. These can be used in patients with PV-SMV occlusion and
patients with SMA involvement [75, 76].
288
R. J. Bello and C. N. Clarke
Arterial Resection andReconstruction
Initial reports of arterial resection during pancreatectomy had shown high complication rates and poor oncologic outcomes. This was related to suboptimal margins
and what are now outdated chemotherapeutic regimens [77]. Improvements in chemotherapy and radiation therapy together with advances in surgical technique have
rekindled the discussion on optimal patient selection and treatment sequencing to
provide benet from curative pancreatectomy involving arterial resection.
In a series of patients with arterial involvement from PDAC, Christians etal.
reported on ten patients undergoing neoadjuvant therapy following curative pancreatectomy with arterial resection. R0 resection was achieved in 85% of the patients
and morbidity was acceptable at 20%. There were no perioperative deaths. At an
average follow-up of 21months, 62% of patients were alive and had no evidence of
recurrence. None of the remaining patients had locoregional recurrence but instead
developed metastatic disease at a median of 33months from pancreatectomy [76].
Similarly, subsequent studies with larger patient cohorts from other high-volume
centers have demonstrated acceptable outcomes and safety proles for pancreatectomy with arterial resection following extensive courses of neoadjuvant therapy [60,
62]. These reports all emphasized the importance of dening surgical eligibility at
the time of diagnosis and reassessing at several stages throughout administration of
neoadjuvant therapy.
One of the challenges in managing patients with borderline resectable PDAC is
the assessment of radiological response on the tumor–vessel interface after neoadjuvant therapy and prior to pancreatectomy. Ferrone etal. documented signicant
discordance between CT imaging and pathology results; patients with adequate
serological response in CA19-9 levels after receiving FOLFIRINOX, with or without chemoradiation, would often lack radiological response in the form of separation of the tumor from critical vessels on restaging CT scans. Intraoperative
pathology would show brosis and no viable tumor, indicating a good tumor
response. Therefore, Ferrone etal. suggested exploration even in the absence of
radiological response on arterial vascular involvement after neoadjuvant therapy.
They advocated for proceeding with resection if there is no viable tumor on intraoperative pathologic assessment and aborting if frozen section is positive for malignancy [62]. We consider it crucial to justify the risks of exploration (i.e., risk of
vascular complication, delay in resuming chemotherapy, effect of negative laparotomy on tumor immunology) with a clear intent for curative resection, with anticipated vascular resection if required.
Summary
Treatment sequencing is a key component to enhance outcomes in patients undergoing treatment for PDAC, with increased focus on neoadjuvant therapy prior to pancreatectomy even in patients with resectable disease. Decisions regarding treatment
modalities, sequencing, and surgical eligibility should be made in a
16 Pancreatic Ductal Adenocarcinoma
289
multidisciplinary setting with input from medical oncology, surgery, radiation
oncology, diagnostic radiology and ideally also including interventional gastroenterology. Improvements in surgical technique and multimodal neoadjuvant therapy
have expanded the pool of patients with PDAC who can undergo potentially curative pancreatic resection. Given the substantial survival benet that these patients
obtain from resection, one of the main goals of PDAC work-up after diagnosis
should be to identify patients who are most likely to undergo surgical resection
(resectable, borderline resectable, and locally advanced type A) and facilitate
sequencing of multimodal therapy. Oncologic outcomes and perioperative safety
are optimized with early surgical decision-making as well as careful follow-up
throughout the receipt of neoadjuvant therapies. In many cases, pancreatectomy
may require complex vascular resection and reconstruction which should be performed only at high- volume pancreatic surgery centers to minimize morbidity and
mortality with these high-risk procedures.
References
1. Cancer stat facts: pancreas. 2020; National Cancer Institute. Available from: https://seer.can-
cer.gov/statfacts/html/pancreas.html
2. Mizrahi JD, Surana R, Valle JW, Shroff RT. Pancreatic cancer. Lancet.
2020;395(10242):2008–20.
3. Tanaka M.Intraductal papillary mucinous neoplasm of the pancreas as the main focus for early
detection of pancreatic adenocarcinoma. Pancreas. 2018;47(5):544–50.
4. Brennan DD, Zamboni GA, Raptopoulos VD, Kruskal JB. Comprehensive preoperative
assessment of pancreatic adenocarcinoma with 64-section volumetric CT. Radiographics.
2007;27(6):1653–66.
5. Balachandran A, Bhosale PR, Charnsangavej C, Tamm EP. Imaging of pancreatic neoplasms.
Surg Oncol Clin N Am. 2014;23(4):751–88.
6. Lee ES, Lee JM.Imaging diagnosis of pancreatic cancer: a state-of-the-art review. World J
Gastroenterol. 2014;20(24):7864–77.
7. Lee JK, Kim AY, Kim PN, Lee MG, Ha HK. Prediction of vascular involvement and resectability by multidetector-row CT versus MR imaging with MR angiography in patients
who underwent surgery for resection of pancreatic ductal adenocarcinoma. Eur J Radiol.
2010;73(2):310–6.
8. Lu DS, Reber HA, Krasny RM, Kadell BM, Sayre J. Local staging of pancreatic cancer: criteria for unresectability of major vessels as revealed by pancreatic-phase, thin-section helical
CT. AJR Am J Roentgenol. 1997;168(6):1439–43.
9. Tamm EP, Loyer EM, Faria S, et al. Staging of pancreatic cancer with multidetector CT in the
setting of preoperative chemoradiation therapy. Abdom Imaging. 2006;31(5):568–74.
10. Brugge WR, Van Dam J. Pancreatic and biliary endoscopy. N Engl J Med.
1999;341(24):1808–16.
11. Ballehaninna UK, Chamberlain RS.The clinical utility of serum CA 19-9in the diagnosis,
prognosis and management of pancreatic adenocarcinoma: an evidence based appraisal. J
Gastrointest Oncol. 2012;3(2):105–19.
12. Tsai S, Mahmoud A, George B, et al. Association of decline in serum Ca19-9 after neoadjuvant
therapy with improved survival among borderline resectable pancreatic cancer patients. J Clin
Oncol. 2013;31(15_suppl):e15082.
13. Tian F, Appert HE, Myles J, Howard JM. Prognostic value of serum CA 19-9 levels in pancreatic adenocarcinoma. Ann Surg. 1992;215(4):350–5.
290
14. Tsai S, George B, Wittmann D, etal. Importance of normalization of CA19-9 levels following
neoadjuvant therapy in patients with localized pancreatic cancer. Ann Surg. 2020;271(4):740–7.
15. Hernandez JM, Cowgill SM, Al-Saadi S, et al. CA 19-9 velocity predicts disease-free survival and overall survival after pancreatectomy of curative intent. J Gastrointest Surg.
2009;13(2):349–53.
16. Hata S, Sakamoto Y, Yamamoto Y, et al. Prognostic impact of postoperative serum CA 19-9
levels in patients with resectable pancreatic cancer. Ann Surg Oncol. 2012;19(2):636–41.
17. Montgomery RC, Hoffman JP, Riley LB, Rogatko A, Ridge JA, Eisenberg BL. Prediction of
recurrence and survival by postresection CA 19-9 values in patients with adenocarcinoma of
the pancreas. Ann Surg Oncol. 1997;4(7):551–6.
18. Meng Q, Shi S, Liang C, et al. Diagnostic and prognostic value of carcinoembryonic antigen in
pancreatic cancer: a systematic review and meta-analysis. Onco Targets Ther. 2017;10:4591–8.
19. Tsai S, Christians KK, Ritch PS, et al. Multimodality therapy in patients with borderline
resectable or locally advanced pancreatic cancer: importance of locoregional therapies for a
systemic disease. J Oncol Pract. 2016;12(10):915–23.
20. Winter JM, Cameron JL, Campbell KA, et al. 1423 pancreaticoduodenectomies for pancreatic cancer: a single-institution experience. J Gastrointest Surg. 2006;10(9):1199–210; discussion 1210–1.
21. Fatima J, Schnelldorfer T, Barton J, et al. Pancreatoduodenectomy for ductal adenocarcinoma:
implications of positive margin on survival. Arch Surg. 2010;145(2):167–72.
22. Neoptolemos JP, Stocken DD, Dunn JA, et al. Inuence of resection margins on survival for
patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the
ESPAC-1 randomized controlled trial. Ann Surg. 2001;234(6):758–68.
23. Bilimoria KY, Talamonti MS, Sener SF, et al. Effect of hospital volume on margin status after
pancreaticoduodenectomy for cancer. J Am Coll Surg. 2008;207(4):510–9.
24. Noone AM, Howlader N, Krapcho M, etal., editors. SEER cancer statistics review, 1975–2015.
Bethesda, MD: National Cancer Institute; 2018 [cited 2018 May 2]. Available from: https://
seer.cancer.gov/csr/1975_2015/, based on November 2017 SEER data submission, posted to
the SEER web site.
25. Varadhachary GR, Tamm EP, Crane C, Evans DB, Wolff RA. Borderline resectable pancreatic
cancer. Curr Treat Options Gastroenterol. 2005;8(5):377–84.
26. Katz MH, Pisters PW, Evans DB, et al. Borderline resectable pancreatic cancer: the importance
of this emerging stage of disease. J Am Coll Surg. 2008;206(5):833–46; discussion 846–8.
27. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.
28. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nabpaclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691–703.
29. Katz MH, Marsh R, Herman JM, et al. Borderline resectable pancreatic cancer: need for standardization and methods for optimal clinical trial design. Ann Surg Oncol. 2013;20(8):2787–95.
30. Tran Cao HS, Balachandran A, Wang H, et al. Radiographic tumor-vein interface as a predictor
of intraoperative, pathologic, and oncologic outcomes in resectable and borderline resectable
pancreatic cancer. J Gastrointest Surg. 2014;18(2):269–78; discussion 278.
31. Leach SD, Lee JE, Charnsangavej C, et al. Survival following pancreaticoduodenectomy with
resection of the superior mesenteric-portal vein conuence for adenocarcinoma of the pancreatic head. Br J Surg. 1998;85(5):611–7.
32. Tseng JF, Raut CP, Lee JE, et al. Pancreaticoduodenectomy with vascular resection: margin
status and survival duration. J Gastrointest Surg. 2004;8(8):935–49; discussion 949–50.
33. Nagakawa T, Kayahara M, Ohta T, Ueno K, Konishi I, Miyazaki I. Patterns of neural and
plexus invasion of human pancreatic cancer and experimental cancer. Int J Pancreatol.
1991;10(2):113–9.
34. Kharofa J, Tsai S, Kelly T, et al. Neoadjuvant chemoradiation with IMRT in resectable and
borderline resectable pancreatic cancer. Radiother Oncol. 2014;113(1):41–6.
R. J. Bello and C. N. Clarke
16 Pancreatic Ductal Adenocarcinoma
35. DeCaprio JA, Mayer RJ, Gonin R, Arbuck SG. Fluorouracil and high-dose leucovorin in previously untreated patients with advanced adenocarcinoma of the pancreas: results of a phase II
trial. J Clin Oncol. 1991;9(12):2128–33.
36. Van Rijswijk RE, Jeziorski K, Wagener DJ, et al. Weekly high-dose 5-uorouracil and folinic
acid in metastatic pancreatic carcinoma: a phase II study of the EORTC GastroIntestinal Tract
Cancer Cooperative Group. Eur J Cancer. 2004;40(14):2077–81.
37. Burris HA 3rd, Moore MJ, Andersen J, et al. 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(6):2403–13.
38. Schüller J, Cassidy J, Dumont E, et al. Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol.
2000;45(4):291–7.
39. Cartwright TH, Cohn A, Varkey JA, et al. Phase II study of oral capecitabine in patients with
advanced or metastatic pancreatic cancer. J Clin Oncol. 2002;20(1):160–4.
40. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for
pancreatic cancer. N Engl J Med. 2018;379(25):2395–406.
41. Von Hoff DD, Ramanathan RK, Borad MJ, et al. Gemcitabine plus nab-paclitaxel is an
active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol.
2011;29(34):4548–54.
42. Frese KK, Neesse A, Cook N, et al. Nab-paclitaxel potentiates gemcitabine activity by
reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov.
2012;2(3):260–9.
43. Khawaja MR, Kleyman S, Yu Z, et al. Adjuvant gemcitabine and gemcitabine-based chemoradiotherapy versus gemcitabine alone after pancreatic cancer resection: the Indiana University
experience. Am J Clin Oncol. 2017;40(1):42–6.
44. Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas-616 patients:
results, outcomes, and prognostic indicators. J Gastrointest Surg. 2000;4(6):567–79.
45. Hishinuma S, Ogata Y, Tomikawa M, Ozawa I, Hirabayashi K, Igarashi S. Patterns of recurrence after curative resection of pancreatic cancer, based on autopsy ndings. J Gastrointest
Surg. 2006;10(4):511–8.
46. Smeenk HG, van Eijck CH, Hop WC, et al. Long-term survival and metastatic pattern of
pancreatic and periampullary cancer after adjuvant chemoradiation or observation: long-term
results of EORTC trial 40891. Ann Surg. 2007;246(5):734–40.
47. Groot VP, Rezaee N, Wu W, et al. Patterns, timing, and predictors of recurrence following
pancreatectomy for pancreatic ductal adenocarcinoma. Ann Surg. 2018;267(5):936–45.
48. Jones RP, Psarelli EE, Jackson R, etal. Patterns of recurrence after resection of pancreatic ductal adenocarcinoma: a secondary analysis of the ESPAC-4 randomized adjuvant chemotherapy
trial. JAMA Surg. 2019;154(11):1038–48. https://doi.org/10.1001/jamasurg.2019.3337.
49. Kalser MH, Ellenberg SS.Pancreatic cancer. Adjuvant combined radiation and chemotherapy
following curative resection. Arch Surg. 1985;120(8):899–903.
50. Douglass H, Nava H, Panahon A, etal. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Gastrointestinal
Tumor Study Group. Cancer. 1987;59(12):2006–10.
51. Hsu CC, Herman JM, Corsini MM, et al. Adjuvant chemoradiation for pancreatic adenocarcinoma: the Johns Hopkins Hospital-Mayo Clinic collaborative study. Ann Surg Oncol.
2010;17(4):981–90.
52. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-uorouracil after
curative resection of cancer of the pancreas and periampullary region: phase III trial of the
EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999;230(6):776–82; discussion 782–4.
53. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and
chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12):1200–10.
54. Abrams RA, Lowy AM, O’Reilly EM, Wolff RA, Picozzi VJ, Pisters PW. Combined modality
treatment of resectable and borderline resectable pancreas cancer: expert consensus statement.
Ann Surg Oncol. 2009;16(7):1751–6.
291
292
55. Christians KK, Tsai S, Mahmoud A, et al. Neoadjuvant FOLFIRINOX for borderline resectable pancreas cancer: a new treatment paradigm? Oncologist. 2014;19(3):266–74.
56. Sohal DPS, Duong M, Ahmad SA, et al. Efcacy of perioperative chemotherapy for
Resectable pancreatic adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol.
2021;7(3):421–7. https://doi.org/10.1001/jamaoncol.2020.7328.
57. Wu W, He J, Cameron JL, etal. The impact of postoperative complications on the administration of adjuvant therapy following pancreaticoduodenectomy for adenocarcinoma. Ann Surg
Oncol. 2014;21(9):2873–81.
58. Labori KJ, Bratlie SO, Andersson B, etal. Neoadjuvant FOLFIRINOX versus upfront surgery
for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial.
Lancet Gastroenterol Hepatol. 2024;9(3):205–17.
59. Chun YS, Milestone BN, Watson JC, et al. Dening venous involvement in borderline resectable pancreatic cancer. Ann Surg Oncol. 2010;17(11):2832–8.
60. Chatzizacharias NA, Tsai S, Grifn M, et al. Locally advanced pancreas cancer: staging and
goals of therapy. Surgery. 2018;163:1053.
61. Takahashi H, Ogawa H, Ohigashi H, et al. Preoperative chemoradiation reduces the risk
of pancreatic stula after distal pancreatectomy for pancreatic adenocarcinoma. Surgery.
2011;150(3):547–56.
62. Ferrone CR, Marchegiani G, Hong TS, et al. Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic
cancer. Ann Surg. 2015;261(1):12–7.
63. Sadot E, Doussot A, O’Reilly EM, et al. FOLFIRINOX induction therapy for stage 3 pancreatic adenocarcinoma. Ann Surg Oncol. 2015;22(11):3512–21.
64. Gillen S, Schuster T, Meyer Zum Büschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and
resection percentages. PLoS Med. 2010;7(4):e1000267.
65. Versteijne E, van Dam JL, Suker M, etal. Neoadjuvant chemoradiotherapy versus upfront surgery for resectable and borderline resectable pancreatic cancer: long-term results of the Dutch
randomized PREOPANC trial. J Clin Oncol. 2022;40(11):1220–30.
66. Chuong MD, Springett GM, Freilich JM, et al. Stereotactic body radiation therapy for locally
advanced and borderline resectable pancreatic cancer is effective and well tolerated. Int J
Radiat Oncol Biol Phys. 2013;86(3):516–22.
67. Mahadevan A, Jain S, Goldstein M, et al. Stereotactic body radiotherapy and gemcitabine for
locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2010;78(3):735–42.
68. Rajagopalan MS, Heron DE, Wegner RE, et al. Pathologic response with neoadjuvant chemotherapy and stereotactic body radiotherapy for borderline resectable and locally-advanced
pancreatic cancer. Radiat Oncol. 2013;8:254.
69. Katz MHG, Shi Q, Meyers J, etal. Efcacy of preoperative mFOLFIRINOX vs mFOLFIRINOX plus hypofractionated radiotherapy for borderline resectable adenocarcinoma of the pancreas: the A021501 phase 2 randomized clinical trial. JAMA Oncol. 2022;8(9):1263–70.
70. Finks JF, Osborne NH, Birkmeyer JD.Trends in hospital volume and operative mortality for
high-risk surgery. N Engl J Med. 2011;364(22):2128–37.
71. Evans DB, George B, Tsai S.Non-metastatic pancreatic cancer: resectable, borderline resectable, and locally advanced-denitions of increasing importance for the optimal delivery of
multimodality therapy. Ann Surg Oncol. 2015;22(11):3409–13.
72. Lassen K, Coolsen MM, Slim K, et al. Guidelines for perioperative care for pancreaticoduodenectomy: Enhanced Recovery After Surgery (ERAS ) Society recommendations. World J
Surg. 2013;37(2):240–58.
73. Takagi K, Yoshida R, Yagi T, et al. Effect of an enhanced recovery after surgery protocol
in patients undergoing pancreaticoduodenectomy: a randomized controlled trial. Clin Nutr.
2019;38(1):174–81.
R. J. Bello and C. N. Clarke