**3. Neoadjuvant treatment**

#### **3.1. Indications**

A preoperative treatment has several theoretical advantages. First of all it delivers systemic therapy to all patients: at least 30% of patients do not receive adjuvant therapy after resection for a variety of reasons [20]. Then, it is shed in a highly perfused tumor bed that allows an in vivo testing of the tumor sensibility to the chemotherapeutic agent. Moreover, NADT should increase the probability of negative margin surgery (R0) and decrease the likelihood of nodal involvement and vascular resection (VR). Finally, it identifies tumors with an aggressive biology and picks out patients who would not benefit from surgery because of early progression, recurrence, or previously undiagnosed metastatic disease. Whether those presumed advantages translate into real world is still under investigation. The role of NADT for PaC, especially for primary resectable ones, still remains controversial among other reasons because a quote of those patients undergoing neoadjuvant treatment will experience severe side effects and complications [21]. A comprehensive meta-analysis provides marginal support to the assumed benefit of contemplating neoadjuvant therapies for patients whose tumor was judged resectable at preoperative staging [22]. Neoadjuvant treatment should always be offered to BLR and LA diseases; nevertheless, since preoperative staging in PaC is far from being accurate, with 22.5% of patients brought to the operating room with curative intent found to be metastatic [6], it is crucial to treat every patient within registered trials.

#### **3.2. Outcomes**

#### *3.2.1. Toxicity*

Unfortunately, every neoadjuvant regimen brings its own risk of toxicity, and a successful resection is more likely in case of completion of NADT [23]. A serious side effect might indefinitely postpone surgery; that is why resectable patients are exposed to a shift from being a surgical patient to never being proposed for cure. This has to be taken into account while proposing such treatment in selected patients. As shown in **Table 2**, it is reported that 29.4–36% of patients will experience grade 3 or 4 adverse effects during preoperative treatment [22, 24, 25], with 6% of patients giving up treatment because of its toxicity [26]. But up to 91% of patients initiated to NADT achieve the intended preoperative protocol [24].

median follow-up of 21.3 months [27], suggesting a systemic undiagnosed or uncontrolled disease. A 2010 meta-analysis shows 3.9% of complete pathologic response, 29.1% partial response, 43.9% stable disease, and 20.8% of progression during NADT [25]. A more recent 2017 meta-analysis confirms those data with partial response or stable disease in 79% of treated patients (20 and 59%, respectively) while in progression in 16% of cases [24]. According to Gillen and coll. Pooled percentages of pathologic response did not vary much in the two groups of initially deemed resectable and non-resectable tumor patients [25]; this may be due to the fact that resectability is defined only by anatomical features, while probably a biological understanding of the disease would enhance clinical staging. Anyhow unfortunately, there are 16–32% of patients that will have to stop treatment because of progression [22, 26].

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Surgery is ideally recommended 4 to 8 weeks after neoadjuvant treatment [4] although it has been postulated that patients with a longer (>10 weeks) interval between RT and CHT and surgery could be more likely to have an improved pathological response, R0 resection, and OS [28]. According to a consensus statement drafted in 1999 [29], "standard" pancreatoduodenectomy includes regional lymphadenectomy around the duodenum and pancreas; "radical" pancreatoduodenectomy includes regional lymphadenectomy plus skeletonization of the proper hepatic artery (PHA), common hepatic artery (CHA), superior mesenteric artery (SMA) between the aorta (AA) and inferior pancreaticoduodenal artery, and the CA; dissection of the anterolateral aspect of the aorta and inferior vena cava (IVC) includes Gerota's fascia; and lastly "extended radical" pancreatoduodenectomy includes "radical" pancreatoduodenectomy and clearance of the anterior AA between the diaphragmatic hiatus (around the CA) and the origin of the common iliac arteries. Currently, extended lymphadenectomy is no more recommended as it increases costs [30], blood loss, and operative time without adding survival or staging advantages [31]. For what concerns vascular involvement, venous resection doesn't affect preoperative mortality even if it may slightly increase morbidity; instead, arterial resection is still under major debate since it seems to have acceptable outcomes only in single high-volume centers' reports [32]. In a French experience, patients that received a venous resection but whose tumor did not infiltrate the vessel at final histology, lived longer either than patients whose tumor eventually infiltrate the vein either than patients who did not require a vascular resection (42 months vs. 24 vs 22 respectively p = .04) [33]. This may even justify extreme positions such as calling upon routine VR during pancreatectomies. According to the latest staging system of the American Joint Committee on Cancer (8th edition), venous infiltration doesn't modify T stage: indeed T1 to 3 stages relies on tumor's dimension and T4 is defined only in case of arterial involvement [34]; therefore, venous resection should not hold back surgeons from performing a pancreatectomy with curative intent.

In a 2010 meta-analysis, surgical exploration after NADT was attempted in 69.5% of patients, but only 50.7% of NADT patients were eventually successfully resected (that is 77.9% of explored patients) [25]. In a more recent meta-analysis, the rate of resected patients raised to

**4. Surgery**

**4.1. Resectability**

#### *3.2.2. Pathologic response*

As seen in **Table 3**, up to 11.3% of BLR or LA PaC presented a complete pathologic response (ypT0) after NADT [27]. In this paper 83% of patients with ypT0 were dead or relapsed at a


**Table 2.** Major toxicity.


† Pancreatic cancers AND periampullary tumors.

**Table 3.** Pathological response.

median follow-up of 21.3 months [27], suggesting a systemic undiagnosed or uncontrolled disease. A 2010 meta-analysis shows 3.9% of complete pathologic response, 29.1% partial response, 43.9% stable disease, and 20.8% of progression during NADT [25]. A more recent 2017 meta-analysis confirms those data with partial response or stable disease in 79% of treated patients (20 and 59%, respectively) while in progression in 16% of cases [24]. According to Gillen and coll. Pooled percentages of pathologic response did not vary much in the two groups of initially deemed resectable and non-resectable tumor patients [25]; this may be due to the fact that resectability is defined only by anatomical features, while probably a biological understanding of the disease would enhance clinical staging. Anyhow unfortunately, there are 16–32% of patients that will have to stop treatment because of progression [22, 26].

#### **4. Surgery**

**3.2. Outcomes**

200 Advances in Pancreatic Cancer

*3.2.1. Toxicity*

*3.2.2. Pathologic response*

PaC AND periampullary tumors.

**Author, year Article type Complete** 

**Table 2.** Major toxicity.

Hashemi-Sadraei, 2017 [27]

Gillen, 2010†

Including complete path. resp.

**Table 3.** Pathological response.

Pancreatic cancers AND periampullary tumors.

\*

†

Gillen, 2010\*

**\***

Unfortunately, every neoadjuvant regimen brings its own risk of toxicity, and a successful resection is more likely in case of completion of NADT [23]. A serious side effect might indefinitely postpone surgery; that is why resectable patients are exposed to a shift from being a surgical patient to never being proposed for cure. This has to be taken into account while proposing such treatment in selected patients. As shown in **Table 2**, it is reported that 29.4–36% of patients will experience grade 3 or 4 adverse effects during preoperative treatment [22, 24, 25], with 6% of patients giving up treatment because of its toxicity [26]. But up to 91% of patients

As seen in **Table 3**, up to 11.3% of BLR or LA PaC presented a complete pathologic response (ypT0) after NADT [27]. In this paper 83% of patients with ypT0 were dead or relapsed at a

initiated to NADT achieve the intended preoperative protocol [24].

Dhir, 2017 [24] Metanalysis 36% Marthey, 2015 [26] Cohort study 26% Andriulli, 2012 [22] Metanalysis 31%

Kapoor, 2014 [37] Prospective 0%

Retrospective 11.3% (of resected

**Author, year Article type Grade 3/4 toxicity**

[25] Metanalysis 29,4%

**pathological response**

patients)

Dhir, 2017 [24] Metanalysis n.a. 20% 59% 16%

Marthey, 2015 [26] Cohort study 5.2% 28% 56% 16% Addeo, 2015 [40] Retrospective 8.8% n.a. n.a. n.a. Andriulli, 2012 [22] Metanalysis n.a. 22%\* 50% 25%

Heinrich, 2008 [38] Phase II trial 0% n.a. n.a. n.a. Kim, 2017 [8] Retrospective 0% 65% 35% 0%

[25] Metanalysis 3.9% 29.1% 43.9% 20.8%

**Partial pathological** 

**Stable disease**

n.a. n.a. n.a.

**Progression**

**response**

Surgery is ideally recommended 4 to 8 weeks after neoadjuvant treatment [4] although it has been postulated that patients with a longer (>10 weeks) interval between RT and CHT and surgery could be more likely to have an improved pathological response, R0 resection, and OS [28]. According to a consensus statement drafted in 1999 [29], "standard" pancreatoduodenectomy includes regional lymphadenectomy around the duodenum and pancreas; "radical" pancreatoduodenectomy includes regional lymphadenectomy plus skeletonization of the proper hepatic artery (PHA), common hepatic artery (CHA), superior mesenteric artery (SMA) between the aorta (AA) and inferior pancreaticoduodenal artery, and the CA; dissection of the anterolateral aspect of the aorta and inferior vena cava (IVC) includes Gerota's fascia; and lastly "extended radical" pancreatoduodenectomy includes "radical" pancreatoduodenectomy and clearance of the anterior AA between the diaphragmatic hiatus (around the CA) and the origin of the common iliac arteries. Currently, extended lymphadenectomy is no more recommended as it increases costs [30], blood loss, and operative time without adding survival or staging advantages [31]. For what concerns vascular involvement, venous resection doesn't affect preoperative mortality even if it may slightly increase morbidity; instead, arterial resection is still under major debate since it seems to have acceptable outcomes only in single high-volume centers' reports [32]. In a French experience, patients that received a venous resection but whose tumor did not infiltrate the vessel at final histology, lived longer either than patients whose tumor eventually infiltrate the vein either than patients who did not require a vascular resection (42 months vs. 24 vs 22 respectively p = .04) [33]. This may even justify extreme positions such as calling upon routine VR during pancreatectomies. According to the latest staging system of the American Joint Committee on Cancer (8th edition), venous infiltration doesn't modify T stage: indeed T1 to 3 stages relies on tumor's dimension and T4 is defined only in case of arterial involvement [34]; therefore, venous resection should not hold back surgeons from performing a pancreatectomy with curative intent.

#### **4.1. Resectability**

In a 2010 meta-analysis, surgical exploration after NADT was attempted in 69.5% of patients, but only 50.7% of NADT patients were eventually successfully resected (that is 77.9% of explored patients) [25]. In a more recent meta-analysis, the rate of resected patients raised to


resected patients regardless of VR, while others reported mortality in PV/SMV resection to be as low as 3% [33]. In literature a great amount of data make it muddler to understand the

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The goal of multimodal treatment is to achieve a margin-free surgery, taking into account that additional resection to achieve negative neck margin after R1 frozen section is not associated to improve survival [43]. In pancreatectomies' specimens the most frequently involved margin is the retroperitoneal one (39%) [6]; that is why VR assumes a central role in academic discussions. In fact among patients requiring VR NADT reduced significantly R1 rate (from 34.9 to 19.6%) [40]. After NADT, intention-to-treat (ITT) R0 rates have been reported to be 23–63% depending on their preoperative assessed resectability [24]. In resected patients R0 rate was estimated by a metaanalysis to be as high as 94%; that is to say that this data comes from nonrandomized trials [35]. Indeed, clear resection margins were present in 40% and 75% of cases in Landry [44] and Palmer's [45] RCTs. Lastly, pathologists have to be aware that after a preoperative treatment what seems to be a tumor-free margin could be only the expression of a reduction of density of tumor cells [46].

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,

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

picture of the actual situation.

**5. Role of adjuvant treatment**

**6. Survival**

all that matters is probably only a correct patient selection.

**4.3. Resection margins**

ITT, intention to treat; PaC, pancreatic cancer; BLR, borderline resectable; LA, locally advanced. \* PaC AND periampullary tumors.

**Table 4.** Resectability.

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 outcomes of selected experiences and meta-analysis.

#### **4.2. Morbidity and mortality**

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 resected patients regardless of VR, while others reported mortality in PV/SMV resection to be as low as 3% [33]. In literature a great amount of data make it muddler to understand the picture of the actual situation.

#### **4.3. Resection margins**

The goal of multimodal treatment is to achieve a margin-free surgery, taking into account that additional resection to achieve negative neck margin after R1 frozen section is not associated to improve survival [43]. In pancreatectomies' specimens the most frequently involved margin is the retroperitoneal one (39%) [6]; that is why VR assumes a central role in academic discussions. In fact among patients requiring VR NADT reduced significantly R1 rate (from 34.9 to 19.6%) [40]. After NADT, intention-to-treat (ITT) R0 rates have been reported to be 23–63% depending on their preoperative assessed resectability [24]. In resected patients R0 rate was estimated by a metaanalysis to be as high as 94%; that is to say that this data comes from nonrandomized trials [35]. Indeed, clear resection margins were present in 40% and 75% of cases in Landry [44] and Palmer's [45] RCTs. Lastly, pathologists have to be aware that after a preoperative treatment what seems to be a tumor-free margin could be only the expression of a reduction of density of tumor cells [46].
