**5. Role of adjuvant treatment**

In several trials a significant benefit of ADT after pancreatectomy has been demonstrated [39], but whether additional adjuvant treatment is necessary in preoperatively treated patients is not clear as it may not provide additional survival benefit [40, 47]. In a Korean series 5.9% of patients undergone NADT and pancreatectomy recurred before having the chance to begin ADT [8]. In a Japanese experience, NADT was found to be a negative factor in predicting failure to achieve ADT therapy along with preoperative prognostic nutritional index, intraoperative blood transfusion, organ/space surgical site infections, and advanced UICC stage; however, this association was not confirmed at multivariate analysis, and only poor prognostic nutritional index, intraoperative blood transfusions, and organ/space surgical site infections were confirmed to be significantly associated with ADT dropout [48]. What is the real weight of NADT in precluding the administration of ADT? An American group reported the administration of ADT to 90% of resected patients after a long-term NADT regimen [23]; thus, all that matters is probably only a correct patient selection.

## **6. Survival**

65%, but reported percentages vary from 26.7% to 89.28% depending on variability of protocols and patients [35]. In fact resection was more likely in resectable patients (73.6%) than in nonresectable ones (33.2%) [25]. In John Hopkins Hospital's experience, recently published, resection in BLR patients after neoadjuvant treatment was achieved in 44% of cases [36], while it was possible only in 26.7% of LA patients in an Indian report [37] versus 89.28% of pancreatectomies in resectable patients of a Swiss trial [38]. Those are single experiences that cannot reflect general reality, and the few existing neoadjuvant RCTs report a protocol achievement range of 18.18–70% [39]. Anyway, after neoadjuvant treatment between 26.5% [8] and 97.7% [40] of patients successfully receiving a pancreatectomy will require a VR. **Table 4** reports resection's

According to the recently reported experience of an Italian group with more than 150 pancreatectomies per year, NADT exposes patients to a reduced incidence of postoperative fistula and hemorrhage; unfortunately, in spite of this, the average clinical burden is increased [41]. Back in 2010 a morbidity of 34.2% with a mortality of 5.3% in eventually resected patients was reported as a meta-analytical data after NADT [25]. Some claimed perioperative mortality to be much higher (6.7–7%) after NADT with FOLFIRINOX [26, 40, 42] compared to upfront

outcomes of selected experiences and meta-analysis.

**4.2. Morbidity and mortality**

**Author, year Article type ITT** 

Epelboym, 2014 [42]

202 Advances in Pancreatic Cancer

Gillen, 2010\* [25]

Sherestha, 2017 [36]

D'Angelo, 2017 [35]

Addeo, 2015 [40]

Marthey, 2015

Kapoor, 2014 [37]

Andriulli, 2012

Heinrich, 2008

**Table 4.** Resectability.

PaC AND periampullary tumors.

[26]

[22]

[38]

\*

**population**

Retrospective Mixed ITT=explored 82.2% 64.3%

Metanalysis Mixed 69.5% 50.7% n.a.

Retrospective BLR 54.9% 44% n.a.

Metanalysis Mixed n.a. 65% n.a.

Retrospective Mixed ITT=explored 77.5% 97.7%

Cohort study LA n.a. 66% n.a.

Prospective LA n.a. 26.7% n.a.

Phase II trial Resectable 93% 89.28% 12.5%

Kim, 2017 [8] Retrospective BLR ITT = explored 85% 26.5%

Metanalysis Mixed 66% 74% (of

ITT, intention to treat; PaC, pancreatic cancer; BLR, borderline resectable; LA, locally advanced.

**Explored/ITT Resected/ITT Vascular resection/**

explored)

**resected**

n.a.

Survival goes hand in hand with successful surgical resection with a wide clear (R0) margin (>1 mm) giving the chance for an OS of 35 months, while R0 < 1 mm of 16 months involved margin (R1) resections of 14 months and unresected patients only 11 months (p < .001) [6]. Even in case of complete pathologic response (ypT0) after NADT and pancreatectomy cure is not guaranteed; indeed, in a series of ypT0 patients, 83.3% were dead or relapsed after a median of 21.3 months [27]. In NADT patients, resection hangs the scales in survival: in a meta-analysis OS in eventually resected patients was 22.78 months versus 9.89 in non-resected patients with


is unreliable. Indeed, there may be relevant tumor regression during NADT around involved vessels despite the absence of radiographic signs of tumor downstaging [54]. Not even PET-CT has shown to be reliable in differentiating benign from malignant disease after NADT [55].

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In Miura' study, while in the ITT analysis, clinically BLR disease was an independent poor prognostic indicator, among resected patients OS did not differ between preoperatively classified resectable and BLR patients [56]. Similarly, OS of previously resected patients (20.87 months) was not better than the overall resected ones (22.78 months) in a recent metaanalysis [35]; this reflects the inadequacy of current preoperative staging and confirms that once resected, preoperative staging doesn't influence patients' outcomes. Once more, our

Supporters claim NADT to increase patients' selection, but unfortunately despite NADT, there is still a proportion of patients early progressing after surgery [8], for those patients we need more accurate staging and prognostic biomarkers in order to avoid useless surgery.

Overall, only 57.7% of PaC patients will receive the intended ADT—of which 24.1% more than 70 days after surgery—and this is mainly due to surgical complications: a wound dehiscence may seem trivial, but it lowers the percentage of patients receiving systemic therapy to 43.6% versus 61.8% in patients without any postoperative morbidity [57]. NADT bypasses this dropout administrating treatment before surgery; the price to pay is that about one-third of patients experiencing major toxicity and about one-fifth progressing, but in resected ones,

That NADT is safe and helpful in upfront technically unresectable patients and is self-evident, which other choices would they have? But how can we know if it is advisable in resectable patients regardless to vascular (whether venous or arterial) or en bloc multi-organ resections? A German group tried to design an RCT comparing NADT versus upfront surgery, in both cases followed by ADT, to rule out the question. Unfortunately, even if a slight increase in OS, R0, and N0 rates was seen in NADT arm, the trial had to be stopped due to slow recruiting; thus, sample size was not reached and results were not significant [58]. According to Mellon and colleagues, patients with BLR or LA PaC and sufficient response to neoadjuvant multi-agent chemotherapy and stereotactic body radiation therapy have similar or improved perioperative and long-term survival outcomes compared to upfront resected patients [59].

The problem dealing with NADT is that RCTs are lacking; the existing three trials conducted on resectable PaC report a protocol achievement of 18.18–70% and an ITT survival of 9.9– 19.4 months [39]. Selected retrospective single-institution experiences over resectable BLR and LA PaC report OS up to 43.4 months in resected patients following chemotherapy or chemoradiation [60]. In a paper comparing NADT in BLR-LA to upfront resected patients, the ITT analysis showed worse survival for the former (17.0 vs. 22.1 mo, p = 0.029); such comparison has little significance because in the first group 61.6% of patients was eventually unresectable, while the upfront surgery group accounted only resected and adjuvant-treated patients [59]. Indeed, there was no significant difference and even a slight trend favoring NADT, in survival between the two groups among only resected patients (33.5 vs. 23.1 mo, p = 0.057) [59].

Histological confirmation of the disease is mandatory before administering NADT even though up to 16% of preoperatively cyto−/histologically diagnosed PaC eventually receive a

efforts have to be straight at bringing patients to a curative surgery.

surgery seems not to be affected by the worst outcomes.

**Table 5.** Survival.

an ITT OS of 16.7 months (please see **Table 5**) [36]. Such results are in line with a high-volume center such as Johns Hopkins Hospital, in which after NADT median overall survival (mOS) of resected patients was 25.8 months versus 11.9 months in eventually non-resected patients [36]. Results in the setting of RCTs aren't equally encouraging with ITT OS ranging 9.9–19.4 months in NADT setting versus 12.5–29.8 months in ADT one [39], but it shouldn't be forgotten that in the former we are dealing with resectable patients, while in the latter with resected ones; therefore, we could make a comparison only including in the latter group also patients who undergone explorative laparotomies. In a retrospective series, thanks to less lymphovascular invasion, less perineural invasion, and lower T and N stages, NADT-treated and NADT-resected patients presented a better median overall survival than primarily resected ones (27.3 months vs. 19.7 months, p < .05) [42]. In their experience, concerning vascular resections, there was no difference among NADT patients between VR+ and VR- in terms of OS [42].

### **7. Discussion**

Every surgery resident is raised with two warnings:

*"Eat when you can, sleep when you can, and don't mess with the pancreas."*

and

*"God put the pancreas in the retroperitoneum so the surgeon won't mess with it."*

Perioperative mortality in pancreatectomies has been as high as 15% in the 1950s–1970s and since then has dropped to 1.5% in selected centers [49]. Nevertheless, pancreatic surgery for PaC has still high in-hospital mortality rates, as highlighted by an analysis of the German national database; it ranges from 12.2% in very-low-volume hospitals (with a median of four resections per year) to 7.1% in high-volume ones (with a median of 105 resections per year) [50]. Surgery is the only chance for cure of patients affected by PaC—and besides it decreases costs compared to palliative treatments [51]—but multimodal treatment is crucial for long-term survival [52]. Therefore, patients' selection has to be accurate since in one hand patients sent to NADT may miss the window for resection and in the other surgical complications may indefinitely postpone systemic treatment. Currently, there are no reliable clinical predictors of resectability [36]: in order not to lose the chance for resection, all patients receiving NADT should be surgically explored unless evident metastatic disease as fibrosis and inflammation can mimic a LA unresectable disease. As Buanes said, "one of the major problems worldwide is the underutilization of surgery in resectable pancreatic cancer" [53], and, especially after NADT, clinical staging is unreliable. Indeed, there may be relevant tumor regression during NADT around involved vessels despite the absence of radiographic signs of tumor downstaging [54]. Not even PET-CT has shown to be reliable in differentiating benign from malignant disease after NADT [55].

In Miura' study, while in the ITT analysis, clinically BLR disease was an independent poor prognostic indicator, among resected patients OS did not differ between preoperatively classified resectable and BLR patients [56]. Similarly, OS of previously resected patients (20.87 months) was not better than the overall resected ones (22.78 months) in a recent metaanalysis [35]; this reflects the inadequacy of current preoperative staging and confirms that once resected, preoperative staging doesn't influence patients' outcomes. Once more, our efforts have to be straight at bringing patients to a curative surgery.

an ITT OS of 16.7 months (please see **Table 5**) [36]. Such results are in line with a high-volume center such as Johns Hopkins Hospital, in which after NADT median overall survival (mOS) of resected patients was 25.8 months versus 11.9 months in eventually non-resected patients [36]. Results in the setting of RCTs aren't equally encouraging with ITT OS ranging 9.9–19.4 months in NADT setting versus 12.5–29.8 months in ADT one [39], but it shouldn't be forgotten that in the former we are dealing with resectable patients, while in the latter with resected ones; therefore, we could make a comparison only including in the latter group also patients who undergone explorative laparotomies. In a retrospective series, thanks to less lymphovascular invasion, less perineural invasion, and lower T and N stages, NADT-treated and NADT-resected patients presented a better median overall survival than primarily resected ones (27.3 months vs. 19.7 months, p < .05) [42]. In their experience, concerning vascular resections, there was no

**Author, year Type of article ITT-OS (months)**

Andriulli, 2012 [22] Metanalysis 16.4 D'Angelo, 2017 [35] Metanalysis 16.7 Sherestha, 2017 [36] Retrospective 15.1

difference among NADT patients between VR+ and VR- in terms of OS [42].

*"Eat when you can, sleep when you can, and don't mess with the pancreas."*

*"God put the pancreas in the retroperitoneum so the surgeon won't mess with it."*

Perioperative mortality in pancreatectomies has been as high as 15% in the 1950s–1970s and since then has dropped to 1.5% in selected centers [49]. Nevertheless, pancreatic surgery for PaC has still high in-hospital mortality rates, as highlighted by an analysis of the German national database; it ranges from 12.2% in very-low-volume hospitals (with a median of four resections per year) to 7.1% in high-volume ones (with a median of 105 resections per year) [50]. Surgery is the only chance for cure of patients affected by PaC—and besides it decreases costs compared to palliative treatments [51]—but multimodal treatment is crucial for long-term survival [52]. Therefore, patients' selection has to be accurate since in one hand patients sent to NADT may miss the window for resection and in the other surgical complications may indefinitely postpone systemic treatment. Currently, there are no reliable clinical predictors of resectability [36]: in order not to lose the chance for resection, all patients receiving NADT should be surgically explored unless evident metastatic disease as fibrosis and inflammation can mimic a LA unresectable disease. As Buanes said, "one of the major problems worldwide is the underutilization of surgery in resectable pancreatic cancer" [53], and, especially after NADT, clinical staging

Every surgery resident is raised with two warnings:

**7. Discussion**

ITT-OS, intention-to-treat overall survival.

**Table 5.** Survival.

204 Advances in Pancreatic Cancer

and

Supporters claim NADT to increase patients' selection, but unfortunately despite NADT, there is still a proportion of patients early progressing after surgery [8], for those patients we need more accurate staging and prognostic biomarkers in order to avoid useless surgery.

Overall, only 57.7% of PaC patients will receive the intended ADT—of which 24.1% more than 70 days after surgery—and this is mainly due to surgical complications: a wound dehiscence may seem trivial, but it lowers the percentage of patients receiving systemic therapy to 43.6% versus 61.8% in patients without any postoperative morbidity [57]. NADT bypasses this dropout administrating treatment before surgery; the price to pay is that about one-third of patients experiencing major toxicity and about one-fifth progressing, but in resected ones, surgery seems not to be affected by the worst outcomes.

That NADT is safe and helpful in upfront technically unresectable patients and is self-evident, which other choices would they have? But how can we know if it is advisable in resectable patients regardless to vascular (whether venous or arterial) or en bloc multi-organ resections? A German group tried to design an RCT comparing NADT versus upfront surgery, in both cases followed by ADT, to rule out the question. Unfortunately, even if a slight increase in OS, R0, and N0 rates was seen in NADT arm, the trial had to be stopped due to slow recruiting; thus, sample size was not reached and results were not significant [58]. According to Mellon and colleagues, patients with BLR or LA PaC and sufficient response to neoadjuvant multi-agent chemotherapy and stereotactic body radiation therapy have similar or improved perioperative and long-term survival outcomes compared to upfront resected patients [59].

The problem dealing with NADT is that RCTs are lacking; the existing three trials conducted on resectable PaC report a protocol achievement of 18.18–70% and an ITT survival of 9.9– 19.4 months [39]. Selected retrospective single-institution experiences over resectable BLR and LA PaC report OS up to 43.4 months in resected patients following chemotherapy or chemoradiation [60]. In a paper comparing NADT in BLR-LA to upfront resected patients, the ITT analysis showed worse survival for the former (17.0 vs. 22.1 mo, p = 0.029); such comparison has little significance because in the first group 61.6% of patients was eventually unresectable, while the upfront surgery group accounted only resected and adjuvant-treated patients [59]. Indeed, there was no significant difference and even a slight trend favoring NADT, in survival between the two groups among only resected patients (33.5 vs. 23.1 mo, p = 0.057) [59].

Histological confirmation of the disease is mandatory before administering NADT even though up to 16% of preoperatively cyto−/histologically diagnosed PaC eventually receive a final pathological diagnosis other than PaC [38], thus receiving a useless neoadjuvant treatment. In Golcher's study pathological diagnosis of PaC at biopsy has been rejected in 4.5% of resected patients (because of the finding of a distal choledochal adenocarcinoma and a duodenal adenocarcinoma) [58].

LA Locally advanced

CRT Chemoradiation

CHT Chemotherapy

VR Vascular resection

IVC Inferior vena cava

GDA Gastroduodenal artery

PHA Proper hepatic artery

CHA Common hepatic artery

SSO Society of Surgical Oncology

CA19.9 Carbohydrate antigen 19.9 CEA Carcinoembryonic antigen

CTCs Circulating tumor cells

positive margin)

RCT Randomized controlled trial

mOS Median overall survival

PS Performance status

ITT Intention to treat OS Overall survival

AHBPA American Heptad-Biliary-Pancreatic Association

R0 No cancer cells seen microscopically at the resection margin

ypT0 Complete pathological response after neoadjuvant treatment

R1 Cancer cells present microscopically at the resection margin (microscopic

SSAT Society of Surgery of the Alimentary Tract

IAP International Association of Pancreatology

PV Portal vein

AA Aorta

NADT Neoadjuvant treatment

SMA Superior mesenteric artery

SMV Superior mesenteric vein

NCCN National Comprehensive Cancer Network

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