Although patients with localized PDAC disease will most benefit from a complete resection of the primary lesion, a number of different factors can affect the decision of surgery when selecting patients. The systemic nature of PDAC at diagnosis, the relatively low chance of long-term survival and the impact of pancreatectomy on quality of life are factors that need to be carefully assessed. Since the majority of these patients have locally invasive and/or micrometastatic disease at the time of operation, they run a high risk of both local and systemic recurrence following an operation with a potentially curative intent and a significant morbidity in 40–65 % of patients and mortality up to 5 % [149, 150]. Furthermore, despite improvements in surgical techniques over the last decades and perioperative patient care, pancreatic surgery is still associated with substantial perioperative morbidity and in-hospital mortality as well as significant impact on complete recovery to a normal quality of life, which can take up to 2–3 months even in the absence of any complication.

This is also important to consider for the formulation of a management plan and the implementation of neoadjuvant therapy through patient evaluation by a multidisciplinary team. Several factors, including stage, overall performance status, tumor biology, influence the final decision and significant comorbidities and age (>70 years) can determine the ability of a patient to tolerate a major operation or a neoadjuvant approach [151]. Extensive metastatic disease at the time of diagnosis, locally infiltrative and rapidly progressing tumors indicate aggressive biology and in general, patients even with an early-stage but aggressive tumor biology are unlikely to benefit from local therapy such as surgical resection. Although, there is still no validated marker to characterize this aggressive biology, low serum CA19-9 levels and wild-type SMAD4 gene status can identify patients with a more favorable tumor profile.

The appropriate operation required for a given patient is mainly determined by the location of the tumor. Pancreaticoduodenectomy (Whipple operation) is the surgery of choice for lesions arising in the head of the pancreas, while a distal pancreatectomy with an en bloc splenectomy may be required for tumors in the tail. However, masses of the neck and body may require a pancreaticoduodenectomy, distal pancreatectomy or, rarely, a total pancreatectomy. Other partial resections, like central pancreatectomy or enucleation techniques do not result in an sufficient lymphadenectomy and are not considered to have a potentially intent. Minimally invasive approaches offer, at least in theory, the merits of less scarring, less postoperative pain, less wound complications, and an earlier return to normal activity and despite the complexity of most pancreatectomies have recently been gaining ground, albeit their role in the management of patients with pancreatic cancer is not yet clear [152]. Pancreaticoduodenectomy morbidity rate has discouragingly remained between in the range of 45 %, even at high volume centers, where results show significantly better outcomes. The common postoperative morbid complications include delayed gastric emptying (15 %), wound infection (8 %), pancreatic fistula (5 %), cardiac events (4 %), abdominal abscess (4 %), bile leakage (4 %), haemorrhage (4 %), sepsis (2 %) and all other complications in less than 2 % of patients. The median survival rate still lingers in less than 2 years (18 months) with a 5-year survival of around 20 %. Negatively affecting factors include positive resection margin, histological grade and tumor size of 3 cm or greater (HR 1.6, p < 0.001) and regional lymphadenopathy (HR 1.3, p = 0.05) [153]. However, emerging non-operative biliary decompression and endoscopic therapies such as stents and non-invasive celiac plexus blocks have facilitated the drastic reduction of elective surgical palliation.

Neoadjuvant therapy remains controversial in pancreatic cancer treatment , although theoretically it presents many advantages, especially in borderline resectable tumors. Among the advantages, it is considered that preoperative chemotherapy allows an early treatment of micrometastatic disease and may also induce tumour regression, reducing the risk of R₁ resection or relapse after surgery. Other potential advantages include a reduced risk of peritoneal tumour implantation during surgery, and the chance of an in vivo assessment of tumour chemosensitivity. Finally, neoadjuvant treatment allows a better patient selection identifying those patients for whom surgery is unlikely to provide any benefit [12]. However, several studies have shown that resection after neoadjuvant chemoradiation (CRT) is associated with increased postoperative stay. It is finally important to note that in order to initiate neoadjuvant therapy, histological confirmation of pancreatic adenocarcinoma is required, unlike surgical resection [154].

Several studies have evaluated the role of neoadjuvant chemotherapy, radiotherapy, or combination of both in resectable pancreatic cancer. A phase II randomized trial studying patients with resectable PDAC receiving gemcitabine alone or a combination of gemcitabine with cisplatin, showed that the response rate and overall survival (OS) were better in combination arm [155]. Neoadjuvant CRT with gemcitabine concomitant to RT was studied on patients with localized pancreatic cancer. Median OS for the whole patients population was 22.7 months while patients who underwent surgery had a median OS of 34 months [156]. A phase II trial evaluated the combination of cisplatin and gemcitabine followed by gemcitabine-based CRT in patients with resectable PDAC. The median OS of all patients from the date of diagnosis was 17.4 months while patients who completed CRT and underwent surgery had a median OS of 31 months [157]. Also paclitaxel in combination with radiotherapy has been tested in patients with resectable PDAC, with moderate results [158]. Overall, patients who completed neoadjuvant CRT and underwent surgery had a higher chance of achieving R₀ resection and a higher overall survival when compared to patients from historical data that underwent surgery without receiving therapy. Nevertheless, CRT may not effectively decrease distant metastasis, as shown by the high rate of distant failure in these studies. Consequently, the role of neoadjuvant therapy in patients with resectable pancreatic cancer has not yet been clearly defined. Prospective controlled randomized trials are needed so as to estimate the benefit of neoadjuvant strategies compared to conventional adjuvant strategies. Presently, the use of neoadjuvant therapies should be considered in the context of a multidisciplinary approach, in order to identify patients at high risk for recurrence.

Borderline resectable pancreatic cancers (BRPC) have been recently defined as cancers with limited involvement of the mesenteric vessels. In this setting, resection may be technically possible, but carries a higher risk of R₁ resection and early recurrence. Chemoradiotherapy is a common approach in such cases and seems to improve the percentage of patients undergoing radical resection. In a study, 7 out of 18 of BRPC patients who received gemcitabine-based chemoradiotherapy were finally resected. Chemoradiotherapy did not increase perioperative morbidity and mortality [159]. In another study, patients were treated with gemcitabine, docetaxel, and capecitabine followed by 5-FU based chemoradiotherapy with IMRT. Eleven patients (64.7 %) out of 17 underwent resection and eight patients (47 %) achieved an R₀ resection. The median progression-free survival and OS were 10.48 months and 15.64 months, respectively [160]. Forty borderline resectable pancreatic cancer patients were treated with combined capecitabine-based chemoradiation. A total of 16 patients (46 %) proceeded to surgery, with 88 % having an R₀ resection and median overall survival of 23 months [161]. A chemoradiotherapy regimen including gemcitabine and oxaliplatin on 68 BRPC and locally advanced pancreatic cancer (LAPC) patients was studied, and R₀ resection was achieved in 36 of 43 patients that underwent surgery. The median overall survival was 18.2 months for all patients and 27.1 months for those who underwent resection [162]. The benefit of neoadjuvant therapies in BRPC was retrospectively reviewed between 1999 and 2006. Patients received neoadjuvant chemotherapy followed by radiation in combination with either 5-fluorouracil (5-FU), gemcitabine, capecitabine, or paclitaxel. Patients who completed the whole therapy including surgery had a significantly better clinical outcome (median OS of 40 months), compared to a median survival of 13 months in unresected patients. These results confirm a positive effect of neoadjuvant treatment in this setting, however, the high rates of disease relapse claim for more effective future treatments [163].

In LAPC patients, neoadjuvant gemcitabine-based combinations have proved to induce higher response rates compared to single agent gemcitabine [164]. A phase II trial, evaluated gemcitabine and oxaliplatin combination in LAPC patients, and after treatment, 39 % of patients underwent curative resection, with a 69 % of R₀ resections. Median OS of patients who underwent tumor resection was 22 months compared with 12 months for those without resection [165]. In another study, patients received either cisplatin, epirubicin, 5-fluorouracil/capecitabine, and gemcitabine or the same regimen with docetaxel substituting epirubicin for 6 months, followed by radiotherapy. A high response rate was observed (47 %) while stable disease was reported in 42 % of patients [166]. A recent systematic review evaluating 111 trials that included 4,394 pancreatic cancer patients, suggested that neoadjuvant treatment may be able to induce conversion to resectability in about one-third of LAPC patients [167]. In patients with borderline resectable or nonresectable pancreatic cancer, neoadjuvant therapy may achieve down-sizing of the tumour, increasing the probability of R₀ resections. Current data is not sufficient to define an optimal regimen in this setting. Combination chemotherapy appears to achieve higher response rates, while there is no strong evidence to support that chemoradiotherapy is superior to chemotherapy alone. More effective chemotherapeutic regimens, like FOLFIRINOX and nab-paclitaxel, are now tested, but the efficacy of these treatments remains to be determined in prospective clinical trials.

Despite the improved understanding of pancreatic cancer biology, the early detection rate remains low. Almost 70 % of patients are diagnosed with advanced disease upon diagnosis and there is no doubt that systemic chemotherapy remains the standard of care in our armamentarium. The available data for first line treatment are robust (OS: 6–11 months), meanwhile the evidence for second line treatment is supported mainly by phase II and retrospective studies with poor survival expectancy (OS: 3–9 months) [183].

Pancreatic cancer carries a dismal prognosis at even the early stage and patients usually have a limited follow-up before they progress on to a more advanced stage. Therefore, much attention is focused upon palliation and symptom control and the decision to treat a patient with more aggressively must always take into account the impact upon a patient’s quality of life (QoL). Toxicities from treatment may also contribute to the patient’s symptom profile despite any clinical benefit response deriving from it. Several comprehensive report forms exist to evaluate patient’s QoL, however, EORTC has developed a disease specific QoL module for pancreatic cancer (EORTC QLQ-PANC26), which has 26 questions and must be used in conjunction with the generic instrument EORTC Quality of Life Questioinnaire-C30 (EORTC C-30). Yet, its utility is strongly restricted both in research and clinical practice, since patients particularly with severe and disabling disease as it is often difficult to complete. Supportive management of symptoms must be initiated early and aggressively to ensure patient comfort with early involvement of the palliative care facilities [211].

Pancreatic cancer frequently presents with pain even as initial symptom at the time of diagnosis. Initial assessment of pain should include evaluation of the intensity, frequency, duration, exacerbating and/or alleviating factors as well as a comprehensive history of current and previous pain medications along with documentation of any side effects encountered on these medications. This should be completed by clinical examination to influence decisions on implementation of the appropriate pharmacologic or procedural interventions. Patient symptoms may also complement as prognostic signs for treatment success and mortality and their response to symptom control may act as predictors of disease extent and response [212].

Albeit, palliative care or pain team should be actively involved in the management of symptoms like pain, the attending physician should be trained and feel comfortable starting the initial analgesic regimen. Opioids are generally thought the mainstay of pharmacologic management of pancreatic cancer pain. Initial therapy shall preferably consist of a short-acting opioid such as morphine or oxycodone. Collateral comorbidities of the patient like chronic kidney damage and/or hepatic impairment should also be taken into account when selecting the appropriate agent. A sustained-release opioid, along with a short-acting opioid for breakthrough pain, may be the next step of actions mainly in patients whose pain has been roughly under control, those with constant pain or those sleeping problems due to pain. Common side effects of opioids include sedation, constipation, pruritus, nausea, xerostomia and testosterone suppression in those on long-term therapy. Constipation is commonly addressed with stool softeners or bowel motility-promoting agents.

However, more advanced techniques might be needed for pain control. The most common and effective procedural intervention for is celiac plexus block [213]. Patients with pain refractory to increasing doses of opioids and those who suffer debilitating opioid-mediated side effects seem to benefit most from a celiac plexus block. Most patients relish a >3 month period of pain relief on initial celiac plexus neurolysis yields, yet, subsequent celiac plexus neurolysis may be feasible in selected patients, its efficacy is seriously mitigated by disease progression. More invasive techniques such as intrathecal delivery of analgesia, via an implantable intrathecal drug delivery systems (IDDSs), might prove helpful especially for patients who have not achieved adequate pain relief. IDDSs managed to control pain, significantly relieve common drug toxicities, and improve survival in patients with refractory cancer pain [214].

Physical symptoms like fatigue, anorexia, cachexia, gastric outlet obstruction, insomnia, decreased appetite, dysgeusia, indigestion and certainly pain heavily impact on pancreatic cancer patients’s psychology. Additionally fear of disease recurrence, severity or advanced stage is pervasive and can render the patient emotionally unstable. Depression is a common condition up to one fifth of patients and become debilitating since data suggest that patients who are depressed are more likely to have suboptimal treatment or poor response. Notably, depression may as well precede initial diagnosis raising that this might equally be a result of chemicals released by the tumor and not just a consequence of the psychological burden of the diagnosis [215]. Regardless of etiology, appropriate early detection and treatment is of paramount importance for the immense suffering it causes.

Pancreatic cancer is a disease with a grim natural history and albeit the aim for health care providers is prolonging life, assisting patients and their families when in distress through the arduous transitions precipitating all too often is equally as important. The multidisciplinary team decision to discontinue treatment is equally disappointing most of the times for both patients and their families as it is for doctors and it should involve patient, family, friends, and the healthcare team. However, it is important to clarify that ending cancer treatment does not necessarily mean ending care. A hospice placement is frequently recommended when prognosis is no longer than 6 months. It addresses all aspects of a patient and family’s needs, including the physical (eg, pain relief), psychological, social, and spiritual or may be given at home. Nowadays, advanced services such as hospital to home care also exist and facilitate the serene transition to home reducing their suffering.

Systemic treatment established by a German group (CONKO-001) and several meta-analyses demonstrated superiority of postoperative gemcitabine compared to surgery alone for patients with resected pancreatic cancer and is the mainstay of adjuvant therapy in Europe; however, combined CRT is preferred in the USA, based on historical trials and single center experiences. Based on ESPAC-3 both weekly gemcitabine and 5-FU/LV can be considered appropriate adjuvant treatment. CRT might have a role to play in node positive, borderline resectable or palliation in advanced unresectable disease. Targeted therapies have largely failed to produce any substantial outcome. The interest for treatment of the metastatic disease has been revived by the introduction of combinations like FOLFIRINOX and nab-paclitaxel for patients with good performance status, absence of biliary obstruction and no infectious complications after addressing the problem of significant expected toxicity. Other alternatives with combination capecitabine and GEM or GEM single agent have conferred some modest benefits. Treatment on relapse or progression is not equally well established, but second line options include 5-FU-based regimens, such as FOLFOX, FOLFIRI or even single-agent capecitabine in patients who cannot tolerate combination treatments.

The majority of patients present with a wide variety of symptoms, which need to be addressed early on and patient and their family requires receiving support, both physical and psychological. Early Palliative Care and Pain team involvement is highly recommended, since prognosis is dismal and relapse highly likely. Health care professionals and attending clinicians need to be actively involved and a network of professional is required to promptly address patient’s needs. Course of events and overall management plan should involve a variety of specialties within the MDT. MDT shall also take the decision for no further oncologic treatment and arrange for patient’s appropriate placement for end of life therapies.