Introduction
Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, currently stands as the third most common cause of cancer related deaths [
1]. In 2008 a total of 70,000 of were diagnosed in Europe [
2,
3]. Rates of new cases of pancreatic cancer have increased on average 0.8% annually over the last ten years. The current 5- and 10-year survival rates at 7.2% and below 4%, respectively [
4].
The aim of the present consensus guidelines is to provide a general overview of the diagnosis, a more global patient´s classification, not just based on performance status, treatment, and management of associated complications of patients with PDAC. These guidelines are the result of expert consensus meetings that took place during the months of September to December 2015 sponsored by Fundación ECO, where a total of forty-two medical oncologists, radiotherapists, surgeons, radiologists, pathologists, endocrinologists, gastrointestinal specialists and palliative care specialists shared their opinions. These recommendations are based on the results of clinical trials, retrospective, observational studies, as well as the group of experts´ opinion (levels of evidence: quality of evidence: I–III; strength of recommendation: A–E) [
5].
PDAC: signs and symptoms
The absence of specific manifestations, together with its biological aggressiveness, results in delayed diagnosis in more than 80% of cases. The most common symptoms include fatigue, anorexia, weight loss, abdominal pain and dark urine [
6]. Sixty to 70% of tumors originate in the pancreatic head, 20–25% in the body and tail and in 10–20% there is a diffuse involvement of the gland [
7]. While tumors in the pancreatic head tend to be diagnosed at earlier stages because of the jaundice associated with bile duct obstruction, tumors in the body and tail are usually detected in advanced stages. Tumor with obstructive jaundice may be associated with palpable gallbladder (Courvoisier sign). Head tumors may also be associated with steatorrhea as a consequence of exocrine pancreatic insufficiency and obstruction of the pancreatic duct. Although with low specificity, the combination of diabetes mellitus (DM) of recent onset associated with weight loss should lead to suspicion PDAC [
8]. About one in 125 (0.85%) patients with new-onset DM presents PDAC, eight times more than expected, compared to the general population [
9]. Patients with newly diagnosed DM without metabolic syndrome and difficult glycemic control should be evaluated to rule out PDAC [
10] (IIB). Special attention should be paid to patients that present the following symptoms: weight loss, abdominal pain, DM of recent onset or with poor disease control. Patients with advanced stages of PDAC may have epigastric palpable mass, hepatomegaly secondary to liver metastases, ascites caused by peritoneal carcinomatosis, pain, vascular and nerve infiltration and/or gastric outlet obstruction. The PDAC is associated with arterial and venous (hypercoagulable state) thrombosis such as Trousseau syndrome (migratory superficial vein thrombosis. PDAC may also be associated with palpable supraclavicular lymph nodes (Virchow), anterior axillary (Irish) or periumbilical mass (Sister Mary Joseph).
Familial PDAC and hereditary PDAC
The International Cancer of the Pancreas Consortium Screening (CAPS) recommends screening of PDAC in high-risk individuals (HRI) or families with familial pancreatic cancer (FPC), although this is not yet included in routine clinical practice [
11] (IIIC). PDAC screening programs should be performed in high-volume centers that have multidisciplinary teams with experience in the screening and treatment of the disease. HRI are considered as those who have at least 5–10 times increased risk of PDAC [
11] and include families with at least two first-degree relatives affected, or ≥3 individuals regardless of the degree of kinship. In addition, subjects with Peutz–Jeghers syndrome, hereditary pancreatitis, or those affected by other hereditary cancer syndromes (germline mutations in the BRCA genes, familial melanoma or colorectal cancer hereditary) with a case of PDAC in the family [
12].
The best screening techniques for HRI is magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) and upper gastrointestinal endoscopic ultrasound (EUS) [
11‐
15] (Algorithm 1).
Screening tests aim to detect small pancreatic solid tumors (≤1 cm), irregular pancreatic duct, and pancreatic precursor lesions such as intraductal papillary mucinous neoplasm (IPMN), which are usually present as cysts [
16]. The prevalence of suspected cystic pancreatic lesions is 33–45% in HRI [
11,
15]. The CAPS recommend starting screening at age 50 years, or ten years before the age of the youngest case in the family [
11] with annual exams if no pancreatic lesions are observed [
11] (IIIB). These intervals could be modified at the discretion of the multidisciplinary tumor committee. If suspicious abnormalities are detected, surgery is indicated although the current available evidence is limited [
11‐
16].
Diagnosis
In patients with suspected PDAC based on medical history and/or physical exam, the primary diagnostic approach to the patient with PDAC is radiological. An abdominal ultrasound is often the first test performed in patients with abdominal pain and/or jaundice. US can detect dilatation of the bile duct or pancreatic duct and the presence of a pancreatic mass. However, the sensitivity for detecting pancreatic tumors is low and ranges between 50 and 70% [
17]. Computer tomography (CT) scan is the gold standard technique in the evaluation of patients with suspected PDAC (IIA). The study of a pancreatic mass must include a biphasic CT performed with an arterial phase (40–50 s) and portal venous phase (65–70 s) [
7,
17‐
19]. In most cases, PDAC is seen in the arterial phase as a hypodense pancreatic lesion, with poorly defined margins [
7]. Furthermore, CT scan detects the vascular involvement (arterial and venous), extra-pancreatic local extension, presence of lymph nodes, and detection of liver or peritoneal nodules [
7]. The availability of a high-quality multidetector CT (preferably ≥16 detectors) combined with experience in the interpretation of these studies has shown a more accurate preoperative staging and better patients´ management [
18]. Magnetic resonance imaging (MRI) has equal sensitivity and specificity than CT for staging PDAC, but its use is not widespread because of its high cost and reduced availability and is usually reserved for difficult cases, cystic neoplasms of the pancreas and to explore biliary anatomy as well [
18]. Radiology report should follow a standard format [
18,
19].
Upper gastrointestinal endoscopy is useful to take biopsies of tumors infiltrating the duodenum as well as for palliative decompression of the duodenum and/or bile duct [
7]. Endoscopic retrograde cholangiopancreatography (ERCP) is restricted to cases with obstruction of the bile duct because is associated with significant adverse effects and has low profitability of achieving a histological diagnosis (20%) [
7]. Endoscopic ultrasound (EUS) is an important complementary examination in the diagnosis and staging of PDAC as it permits examining the primary tumors, relationship with neighboring structures as well as obtaining tissue for pathological diagnoses [
19]. The sensitivity and specificity of EUS-guided tumor fine needle aspiration (FNA) are 90 and 98%, respectively [
20]. It should be noted, however, that patients with clinical and radiological suspected PDAC with resectable do not need a pathological diagnoses before surgical resection (IIIB). Pathological diagnoses are needed in patients with atypical presentation and in those with locally advanced disease that are managed with chemotherapy and/or radiation therapy (IIIB).
Pathological diagnoses and classification
In the presence of suspicious lesions that are resectable, a tumor biopsy prior surgery is not required. Likewise, because of the complexity to obtain it as well as the limitations on its interpretation an intraoperative biopsy is not required [
7,
21] (IIIB). A pathological diagnosis is always required in patients with unresectable or borderline lesions to be managed with chemotherapy and/or radiation therapy as well as in patients with amenable to treatment with metastatic disease [
21] (IIIB).
The technique of choice to obtain tissue for pathological diagnoses depends on the location of the lesion and the stage of the disease. For primary tumors, a EUS-FNA is the safest procedure with highest sensitivity and specificity that can also provide additional staging information [
22]. In patients with metastatic liver disease, a percutaneous US- or CT-guided biopsy is the procedure of choice [
7,
21] (IIIB). If a biopsy does not confirm malignancy, it should be repeated atleast once. If during surgery the tumor is unresectable, histological diagnosis should be made (IIIB).
Table
1 summarizes the histopathologic classification of PDAC tumors. The most common type (95%) is ductal adenocarcinoma of the pancreas, referred to as pancreatic cancer. These tumors originate in ductal epithelium, have glandular differentiation, may produce mucin, and are associated with a significant desmoplastic reaction. There are no specific diagnostic markers to differentiate PDAC from other adenocarcinomas though reactive glands, a CK7+/CK20− profile, while not specific, supports a pancreatic origin.
Table 1
Pathological diagnosis
Classification of pancreatic tumors (WHO 2010 classification) |
Benign
|
Acinar cell cystadenoma |
Serous cystadenoma |
Premalignant lesions
|
Pancreatic intraepithelial neoplasia type 3 (PanIN-3) |
Intraductal papillary mucinous neoplasm with low or intermediate grade dysplasia |
Intraductal papillary mucinous neoplasms |
High-grade dysplasia |
Tubulo-papillary intraductal neoplasia |
Mucinous cystic dysplasia neoplasia with low or intermediate grade |
Mucinous cystic neoplasm with high-grade dysplasia |
Malignant
|
Ductal adenocarcinoma |
Adenosquamous carcinoma |
Colloid carcinoma (non-cystic mucinous carcinoma) |
Hepatoid carcinoma |
Medullary carcinoma |
Cell carcinoma signet ring |
Undifferentiated carcinoma |
Undifferentiated carcinoma with osteoclast-like giant cells |
Acinar cell carcinoma |
Cystoadenocarcinoma acinar cells |
Intraductal papillary mucinous neoplasm or associated with invasive carcinoma |
Mixed acinar-ductal carcinoma |
Mixed acinar-neuroendocrine carcinoma |
Mixed-neuroendocrine carcinoma acinar-ductal |
Mixed ductal-neuroendocrine carcinoma |
Mucinous cystic neoplasm associated with invasive carcinoma |
Pancreatoblastoma |
Serous cystoadenocarcinoma |
Pseudopapillary or solid neoplasia |
Neuroendocrine neoplasms |
Pancreatic neuroendocrine microadenoma |
Neuroendocrine tumor (NET) |
Pancreatic, not functioning G1, G2 NET |
G1 NET |
G2 NET |
Neuroendocrine carcinoma (NEC) |
Large cell NEC |
Small cell NEC |
NET serotonin producer (carcinoid) |
Gastrinoma |
Glucagonoma |
Insulinoma |
Somatostatinoma |
VIPoma |
Mature teratoma |
Mesenchymal tumors |
Lymphomas |
Metastasis |
Biomarkers
Although many biomarkers have been studied for PDAC, only carbohydrate antigen 19.9 (CA 19.9) has proven useful and therefore, it is the only biomarker routinely used [
23] (IA). For diagnoses, it has a sensitivity ranging between 70 and 92% and a specificity of 68–92% depending on tumor size. False positive results are associated with benign diseases such as pancreatitis, cirrhosis, acute cholangitis, and other diseases causing of cholestasis. Determining CA 19.9 is a complementary test in the diagnoses and management of PDAC [
24]. In patients with resectable disease, plasma levels >100 U/mL values predict the presence of occult metastatic disease. In advanced disease, elevated CA 19.9 is considered as unfavorable prognostic factor [
25,
26]. However, given its low positive predictive value, particularly in asymptomatic individuals, is not recommended as a screening marker [
27].
Timeline for diagnosis and management
Because PDAC is very aggressive, it is recommended to reduce the diagnostic time as much as possible to rapidly initiate treatment [
28]. In a study in patients with advanced PDAC it was estimated that the average doubling time of pancreatic tumor was 40–60 days [
29]. A month from the onset of the first symptoms or suspicious signs is a reasonable goal (IIIB).
The National Cancer Strategy Health System (2010) states that the time from therapeutic decision until the actual start of treatment should be less than 2 weeks for surgical treatment, one week for chemotherapy and 4 weeks (including treatment planning) for radiation therapy [
30] (IIIB). Strategies to minimize time to diagnoses include raising awareness in the general population and among health professionals, rapid diagnostic protocols for patients with suspected lesion in primary care settings as well as preferential referral pathways to specialize care and treatment centers. PDAC, like any other complex tumor, should be managed in high referral centers by multidisciplinary teams: Medical oncologists, pathologists, radiotherapist, GI specialist, surgeons and radiologists [
30] (IIIB).
Staging and disease classification
Pancreatic cancer can be staged, based on imaging and pathological studies, in stages as per the TNM classification [
31,
32]. However, from a management perspective, patients are better classified based on the extension of disease in resectable, borderline resectable, locally advanced unresectable and metastatic (IIIA).
In addition, from a treatment perspective, patients with locally advanced/metastatic disease are further classified as: (a) candidate to chemotherapy treatment without limitations; (b) candidate for chemotherapy with limitations and (c) not candidate for treatment with chemotherapy (Table
2) [
6,
33‐
37] (IIIB).
Table 2
Patients’ classification, according to treatment perspective (IIIB)
Patient suitable for chemotherapy treatment without limitations | The presence of ALL the following factors ECOG 0–1 Age ≤75 years Bilirubin ≤1.5 ULN Good nutritional status (serum albumin >2.5 mg/dl, weight lost <10% over the last 3–6 months and BMI >20 kg/m2) Lack of co-morbidities |
Patient suitable for chemotherapy with limitations | The presence of AT LEAST ONE of the following factors ECOG 2 (which can lead to KPS 70%) Age >75 years Mild to moderate neurological or endocrine-metabolic organ dysfunction; in case of liver dysfunction, hyperbilirubinemia >1.5 × ULN (once optimized if obstructive causes are present, for example with biliary stent) marks the degree of dysfunction. It is considered appropriate to adjust the dose, for example, using GEM at 600-800 mg/m 2 and nab paclitaxel 75–100 mg/m 2) [ 37] Cardiac dysfunction, especially a recent ischemic event; acute, symptomatic, severe TED such as PE with hemodynamic instability or DVT with risk and limb amputation [ 38] BMI <20 kg/m2 or >10% weight loss in 3–6 months |
Patient not suitable for chemotherapy treatment | The presence of AT LEAST ONE of the following factors ECOG 3-4 (which may result in KPS ≤ 60%). Active treatment will be initiated in patients with ECOG 3 secondary to the disease (not to their previous comorbidities) without any severe organ dysfunction, thus moving this subgroup of patients to the “candidate for chemotherapy treatment with limitations” group Severe organ dysfunction: neurological (e.g., severe cognitive impairment, Alzheimer’s type); endocrine-metabolic, infectious (uncontrolled HIV), renal, hepatic dysfunctions, etc |
Practical considerations in treatment decision process
The treatment plans for patients with PDAC patients should be made individually. A complete staging process is essential to determine the extent of the tumor that drives treatment plan and prognosis. In parallel, patient´s status, which is linked to its ability to tolerate an aggressive treatment, should be defined. This includes the functional status as determine by the Karnofsky Performance Scale (KPS) and/or the Eastern Cooperative Oncology Group (ECOG). Patients with KPS of less than 60–70% or ECOG less than 0–1 are limited to receive aggressive chemotherapy. For elderly patients, it is also advisable to use geriatric scales such as the Barthel scale that assesses the degree of autonomy in basic activities of daily living [
37]. The assessment of nutritional status as measured by physical exam (weight, body mass index, presence of edema), recent weight lost (>10% over 6 months); plasma protein levels (albumin, prealbumin, transferrin) is crucial [
38]. Validated nutritional scales such as Mini Nutritional Assessment are useful in this regard. In addition, a life expectancy of >3 months is usually needed to administer cancer treatment. Mechanical problems caused by tumor masses such as bile duct and bowel obstruction need to be assessed and corrected prior to treatment commencement. Finally, patient priorities and preferences need to be considered (IIIA).
Supportive care
Supportive care aims to improve symptoms, reduce hospital admission and preserve quality of life. Proper symptomatic management is critical to allow administration of chemotherapy and radiotherapy. Symptomatic management should be accomplished in a multidisciplinary fashion. In this section, we will describe the most common approach to diagnosis and management of the most common symptoms of PADC.
Up to 75% of patients with tumors in the head of the pancreas develop bile duct obstruction which results in jaundice, itching cholangitis and hepatic dysfunction. If untreated, hepatic failure may ensure [
98]. While surgical management had been the preferred approach in the past, particularly coledocoenterostomy, the high mortality of these techniques together with the excellent results obtained with endoscopic approaches has resulted in the preference of endoscopic management [
99]. The preferred approach is endoscopic stent (via ERCP) [
100]. Percutaneous transhepatic colangiopancreatography with stent placement is associated with higher risk of infectious complications and bleeding, being only recommended for patients in whom the endoscopic approach is not feasible [
101]. Plastic stents have a life span of about four months and are only recommended for patients with expected short survival. Patients with longer expected survival should be treated with metal stents that have a longer functionality [
102]. Surgical management is only recommended for patients who undergo a laparotomy for other reasons. Bile duct drainage is clearly recommended in patients who are scheduled for preoperative chemotherapy, those with cholangitis, or those in whom surgical resection is expected to be delayed. However, patients with moderate bilirubin elevation scheduled to undergo surgery can be safely operated without drainage [
103‐
105].
Ten to twenty-five per cent of patients develop duodenal obstruction which is associated with severe symptoms and deterioration of quality of life. The most common approach nowadays is the endoscopic placement of an expansible metallic stent. This approach results in over 90% success with very few complications. The preferred surgical treatment is a gastric jejunonostomy which is only recommended in very selected patients because of high morbidity and mortality when performed as a treatment modality [
106]. Prophylactic gastrojejunostomy should be considered in patients with non-resectable tumors who undergo an exploratory laparotomy. Endoscopic stents are associated with rapid recovery of oral intake, less morbimortality and a shorter hospital stay [
107,
108]. In contrast, surgical treatment is associated with better long term outcome. For this reason surgery is only considered for patients with expected long survival. All these recommendations achieve a level of evidence IIB.
Fifty to sixty per cent of patients with PADC develop some short of pain. These patients need intensive treatment, with both pharmacological and non-pharmacological approaches [
109]. It is important to consider the precise cause of the pain, such as for example bowel obstruction, liver or bone metastasis, or secondary to chemotherapy (neuropathy, mucositis, enteritis) [
110‐
113]. Table
4 summarizes the most important approaches for pain management (IIA).
Table 4
Pain management strategies (IIA)
Mild pain | NSAIDs: Taking into account maximum doses and side effects (gastrointestinal bleeding, nephrotoxicity [ 110] acetaminophen |
Moderate/severe pain | Opioids: any opioid as first choice, except for methadone (secondary choice). Methadone has great benefit in neuropathic pain due to its anti NMDA effect. Should be administered by trained personnel |
Other treatments |
Adjuvant treatment/co-analgesics | Corticosteroids Gabapentine (if neuropathic pain) |
Intrathecal catheters | To manage moderate to severe pain Lower frequency of secondary adverse events, with better pain control [ 111] First choice: hydromorphone, ziconotide, local anesthetic Severe neuropathic pain: baclofen, clonidine |
Miscellaneous (little evidence) | Other therapies: phentolamine, capsaicin, cryoablation, acupuncture |
Radiotherapy | Indicated for management of refractory pain, especially in patients with good performance status and localized pain caused by isolated metastases or pancreas and adjacent structures involvement |
Celiac plexus block [ 112] | Provides better analgesic control (benefit in >80% of the patients) and/or decreases the opioid dose when compared to standard analgesic treatment Cause a disruption in the pain signaling by an average of 3 months It can be performed via percutaneous under ultrasound control, surgical or endoscopic by ultrasound. In terms of technique, there isn’t enough evidence to make any recommendations Side effects are rare (transient hypotension, constipation or diarrhea) There is no evidence to recommend the timing for the blockage (early, at diagnosis, or late when there is poor pain control) There is no evidence that increases survival In the clinical practice celiac plexus block is reserved for patients with poor pain control despite escalation with opioids or for those with opioid related secondary adverse events [ 113] There are limited data regarding the repeated use of celiac plexus block (pain relief is achieved in 29% of the patients) |
Malnourishment is very common in patients with PADC secondary to problems with intake as well as cancer-associated cachexia. Frequent assessment of nutritional status is recommended, being Patient-Generated Subjective Global Assessment (PG-SGA) the most common scale used in oncology [
114]. Intervention ranges from dietary counseling, dietary supplements and enteral feeding. Parenteral nutrition is only recommended as a temporary approach in patients with transient inability for enteral feeding with good general status. For patients scheduled to undergo surgery who present with severe malnutrition (weight loss >10% in 6 months, BMI <18.5 kg/m
2 and serum albumin <3 g/dl) it is recommended to provide nutritional support by dietary supplements, enteral feeding or parenteral feeding for 7–14 days. More than 50% with PADC have pancreatic exocrine insufficiency. This problem usually presents as esteatorrhea. Optimal substitutive treatment with substitute pancreatic enzymes is recommended (25,000–150,000 units per meal intake) [
115].
Cachexia is a multifactorial syndrome characterized by permanent loss of lean body mass. It does not respond to conventional nutritional support and leads to progressive functional deterioration. 20 to 80% of patients with PADC have cachexia, being more common in advance disease [
116]. It is a poor prognosis factor and unfortunately, there is no effective treatment once established. Identification of patients in a pre-cachexia stage were multimodality approach may reverse the symptoms is critical [
117]. Megestrol acetate and high dose steroids are approved for this condition. However, in case of megestrol acetate, side effects such as thrombotic episodes limit its universal recommendation [
118]. All these nutritional support recommendations achieve a level of evidence of IIB.
Thromboembolic disease (TED) is one of the most common complications, with an incidence of 20–35% [
119]. Its etiology is multifactorial, being associated with poor prognosis, particularly in patients with early thrombosis. The risk of TED increase in the perioperative period in patients with advanced disease and in those treated with chemotherapy. An elevated D-dymer, poor performance status, central catheter and absence of prophylaxis increases the risk. The Khorana index is useful to identify high risk patients [
120]. In randomized clinical trials, prophylaxis of deep venous thrombosis (DVT) in patients with PDAC resulted in significant decrease in the rate of thrombosis, with no impact on survival [
121,
122]. Routine prophylaxis of thrombosis is not recommended in the ambulatory setting [
123] (IA). In patients with a Khorana index ≥3 and no risk of bleeding, prophylaxis with low molecular weight heparin could be considered (IIB). Hospitalized patients and those who underwent surgery treatment with low molecular weight heparin are recommended for at least 6 months (IIA).