**2. Definition of borderline resectable pancreatic cancer**

In origin the term "marginally resectable" pancreatic cancer was used for tumors without a 180° free fat plane around SMA, SMV, or PV for at least 1 cm [12]; this outlined a tumor with a high probability of positive-margin surgery. In the following years, several revisions took place, and the term "borderline resectable" was adopted, but still there is no universal consensus on its definition.

#### **2.1. Anatomic criteria**

The pancreatic glands lay in the deepest abdomen in direct contact with several major vascular structures. It is encased between the mesenteric root and the two main splanchnic arteries.

**1. Introduction**

196 Advances in Pancreatic Cancer

**2.1. Anatomic criteria**

By 2030 pancreatic cancer (PaC) is expected to be the second cancer-related cause of death [1]. Its 5-year survival in nonmetastatic stages currently ranges between 3 and 14% [2] regardless of treatment. Surgery remains the only chance for cure since the 5-year survival in T1 N0 resected patients reaches 55.2% [3]; therefore, the standard of care advocates a surgery-first approach in case of resectable disease followed by adjuvant treatment (ADT), but neoadjuvant approaches are spreading either in resectable or borderline resectable (BLR) and locally advanced (LA) patients. The National Comprehensive Cancer Network (NCCN) states that there is limited evidence to recommend specific neoadjuvant regimens off-study [4]. While the only choice in LA PaC is a locoregional chemoradiation (CRT) or systemic chemotherapy (CHT) and subsequent revaluation, for resectable and BLR, we must choose between a surgery-first approach and a neoadjuvant treatment (NADT). Over 40% of patients who have clinically a resectable disease are found unresectable at surgery, even though this percentage drops to 20% if a diagnostic laparoscopy is added to the preoperative diagnostic panel [5]; one out of five patients are eventually misdiagnosed as resectable or BLR while having a LA disease. Even in a high-volume referral hospital, the percentage of successfully resected patients at surgical exploration is as low as 51% [6]. Results of first-line pancreatectomy may be very poor with only 20% of patients receiving radical surgery and 80% presenting tumor within 1 mm from margin or direct microscopic margin infiltration [7]. In a Korean series, 9.1% of patients presenting with PaC diagnosis were clinically staged as BLR [8], about 27% of whom required a vascular resection (VR) in order to achieve their pancreatectomy [9], but histological invasion of resected vessels is confirmed only in 56.7% of specimens [10]. Finally, up to 28% of successfully resected patients will not undergo ADT because of surgical morbidity, poor performance status, refusal, or early recurrence [10]. As Buchler said, unfortunately available evidences supporting NADT come from retrospective studies in which treatment protocols vary greatly and patient cohorts are often mixed with resectable, BLR, and LA [11]. Whereas features of a metastatic disease are evident, dealing with PaC and NADT, a foreword has to be spent to clarify the terminology "resectable," "borderline resectable," and "locally advanced." To that end, we will first focus on the definition of borderline resectable disease

and then analyze the outcomes of NADT from a surgical point of view.

**2. Definition of borderline resectable pancreatic cancer**

In origin the term "marginally resectable" pancreatic cancer was used for tumors without a 180° free fat plane around SMA, SMV, or PV for at least 1 cm [12]; this outlined a tumor with a high probability of positive-margin surgery. In the following years, several revisions took place, and the term "borderline resectable" was adopted, but still there is no universal consensus on its definition.

The pancreatic glands lay in the deepest abdomen in direct contact with several major vascular structures. It is encased between the mesenteric root and the two main splanchnic arteries.

**Figure 1.** Schematic representation of pancreatic vascular relationships. AA, Aorta; IVC, inferior vena cava; PHA, proper hepatic artery; PV, portal vein; SMV, superior mesenteric vein; SMA, superior mesenteric artery; IMV, inferior mesenteric vein; SV, splenic vein; SA, splenic artery; LGA, left gastric artery; CA, celiac axis; CHA, common hepatic artery; GDA, gastro-duodenal artery.

With the PV/SMV-SMA plane being its bed and the celiac trunk being its roof, resectability and thus possibility of cure are played in few millimeters. As shown in **Figure 1**, PaC may arise in the head, body, or tail of the pancreas; therefore, respectability definition differs along with its location whether on the right of the left border of PV/SMV (head) or on the left of the left aortic border (tail) or in between (body). In surgery few things are technically impossible; this is heavily surgeon-dependent because it relies in its skills and will. That is why several institutions/associations have tried and classified PaC resectability depending on its involvement of nearby structures. In **Table 1** the anatomic criteria for definitions of borderline resectable disease from the classifications of five major institutions are shown: MD Anderson Cancer Center [9], American Hepato-Biliary-Pancreatic Association/Society of Surgery of the Alimentary Tract/Society of Surgical Oncology (AHBPA/SSAT/SSO) [13], Alliance A021101 [14], IAP [3], and NCCN [4]. Any situation with a more extensive vascular involvement will obviously be classified under the "locally advanced/unresectable" definition, whereas a less extensive one will define a resectable disease. Despite the effort to standardize definitions and make patients and features comparable among radiologist and surgeons, in some classifications, terms like "allowing for safe reconstruction" still appear increasing confusion among professionals and trials. It is interesting how some may consider a unique SMV/PV <180° involvement that implies a venous resection, as a resectable disease, whereas an arterial involvement is always considered at least borderline resectable; this is due to the surgical


implications of venous and arterial resections, as the former does not increase either postop-

The Role of Neoadjuvant Therapy in Surgical Treatment of Pancreatic Cancer

http://dx.doi.org/10.5772/intechopen.76750

199

Besides anatomical features, PaC may have an intrinsic undiagnosed risk of early recurrent or micrometastatic disease linked to its biology; indeed, early recurrence occurs in 25% of resected patients [16], thus making surgery ineffective. Herein, some examples of biomarkers are predicting more aggressive disease. Preoperative CA19.9 > 300 U/ml and tumor size >3 cm [16], preoperative CEA >3 ng/ml and CA19.9 > 75 U/ml, N+ disease, and T3–T4 [17] are independent negative prognostic factors. Moreover, patients presenting with local disease have a 22% of SMAD-4 loss versus 78% of patients with metastatic disease [18]. In an era of tailored treatments, it should be reminded that every patient and every disease have their own characteristics that have to be taken into account in the therapeutic decision-making. Lately, circulating tumor cells have been investigated as prognostic biomarkers, three or more CTCs/4 ml were an independent prognostic factor for the overall survival, and it accurately predicted occult metastatic disease [19]. That is why during the 20th meeting of the International Association of Pancreatology held in Sendai in 2016 a consensus of borderline resectable definition has been drawn up that includes biological and conditional criteria. Biological criteria are a CA19.9 above 500 IU/ml and regional lymph node metastasis proven by biopsy or PET-CT. Conditional host-related criteria depends on the patient's performance status defined by a PS score of 2 or more [3]. Thus, patients satisfying at least either an ana-

tomic, biologic, or conditional criteria are classified as borderline resectable.

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.

erative morbidity or mortality [15].

**3. Neoadjuvant treatment**

**3.1. Indications**

**2.2. Biologic criteria**

BR, borderline resectable; PV, portal vein; SMV, superior mesenteric vein; SMA, superior mesenteric artery; CA, celiac artery; CHA, common hepatic artery; PHA, proper hepatic artery; AA, aorta; GDA, gastroduodenal artery; IVC, inferior vena cava; TVI, tumor-vessel interface.

**Table 1.** Anatomic criteria for borderline resectable disease.

implications of venous and arterial resections, as the former does not increase either postoperative morbidity or mortality [15].

#### **2.2. Biologic criteria**

International consensus IAP [3] BR-PV (SMV/PV involvement alone):

NCCN Guidelines [4] VENOUS

198 Advances in Pancreatic Cancer

Intergroup criteria Alliance

AHBPA/SSO/SSAT consensus

vena cava; TVI, tumor-vessel interface.

**Table 1.** Anatomic criteria for borderline resectable disease.

A021101 [14]

statement [13]

• SMV/PV: tumor contact 180° or greater or bilateral narrowing/occlusion, not

• SMA, CA: tumor contact of less than 180° without showing deformity/stenosis; • CHA: tumor contact without showing tumor contact of the PHA and/or CA.

• Solid tumor contact with the SMV or PV of >180°, contact of ≤180° with contour irregularity of the vein or thrombosis of the vein but allowing for resection and

• Solid tumor contact with CHA without extension to CA or hepatic artery bifurca-

• Solid tumor contact with the CA of >180° without involvement of the AA and with intact and uninvolved GDA thereby permitting a modified Appleby

• a TVI with SMV or PV ≥180° of the circumference of either vein's wall or short-

• Venous involvement of the SMV/PV demonstrating tumor abutment with or without impingement and narrowing of the lumen, encasement of the SMV/PV but without encasement of the nearby arteries, or short segment venous occlusion resulting from either tumor thrombus or encasement but allowing for resection

• GDA encasement up to the CHA with either short segment encasement or direct

• Tumor abutment of the SMA not to exceed >180° of the circumference of the

• Tumor abutment or encasement (>180° of the circumference of the vessel) of a

• Short-segment occlusion of the SMV, PV, or SMV-PV confluence amenable to

segment occlusion of either vein amenable to reconstruction;

• a TVI with SMA <180° of the circumference of the vessel wall.

abutment of the CHA, without extension to the CA.

MD Anderson Cancer Center [9] • Tumor abutment (<180° of the circumference of the vessel) of the SMA or CA;

vascular resection and reconstruction. BR, borderline resectable; PV, portal vein; SMV, superior mesenteric vein; SMA, superior mesenteric artery; CA, celiac artery; CHA, common hepatic artery; PHA, proper hepatic artery; AA, aorta; GDA, gastroduodenal artery; IVC, inferior

short segment of the CHA;

exceeding the inferior border of the duodenum. • SMA, CA, CHA: no tumor contact/invasion.

• Solid tumor contact with the inferior vena cava (IVC).

tion allowing for resection and reconstruction. • Solid tumor contact with the SMA of ≤180° • Solid tumor contact with variant arterial anatomy

• Solid tumor contact with the CA of ≤180°

• any TVI with CHA amenable to reconstruction;

BR-A (arterial involvement):

reconstruction

If head/uncinate process:

ARTERIAL

If body/tail:

procedure.

and reconstruction.

vessel wall.

Besides anatomical features, PaC may have an intrinsic undiagnosed risk of early recurrent or micrometastatic disease linked to its biology; indeed, early recurrence occurs in 25% of resected patients [16], thus making surgery ineffective. Herein, some examples of biomarkers are predicting more aggressive disease. Preoperative CA19.9 > 300 U/ml and tumor size >3 cm [16], preoperative CEA >3 ng/ml and CA19.9 > 75 U/ml, N+ disease, and T3–T4 [17] are independent negative prognostic factors. Moreover, patients presenting with local disease have a 22% of SMAD-4 loss versus 78% of patients with metastatic disease [18]. In an era of tailored treatments, it should be reminded that every patient and every disease have their own characteristics that have to be taken into account in the therapeutic decision-making. Lately, circulating tumor cells have been investigated as prognostic biomarkers, three or more CTCs/4 ml were an independent prognostic factor for the overall survival, and it accurately predicted occult metastatic disease [19]. That is why during the 20th meeting of the International Association of Pancreatology held in Sendai in 2016 a consensus of borderline resectable definition has been drawn up that includes biological and conditional criteria. Biological criteria are a CA19.9 above 500 IU/ml and regional lymph node metastasis proven by biopsy or PET-CT. Conditional host-related criteria depends on the patient's performance status defined by a PS score of 2 or more [3]. Thus, patients satisfying at least either an anatomic, biologic, or conditional criteria are classified as borderline resectable.
