Pancreatic cancer – still particularly aggressive and deadly

Pancreatic cancer is the seventh most common cancer diagnosis in Switzerland. However, it ranks fourth in terms of mortality, which illustrates the aggressiveness of the tumor. Various studies, especially in the field of chemotherapy, are ongoing.

Prevention, early detection and the development of multimodal treatment concepts can reduce the incidence of some tumor types and improve survival. Pancreatic cancer differs from many tumor diseases in its increasing frequency and aggressiveness.

Epidemiology

The incidence of pancreatic cancer is increasing. In 1990, pancreatic cancer was diagnosed in 845 patients in Switzerland; incidence 12 per 100,000 inhabitants. In 2014, the diagnosis was made 1338 times; incidence 16 per 100,000 inhabitants (Fig. 1) [1]. This makes pancreatic cancer the seventh most common cancer diagnosis [1].

However, in terms of mortality, pancreatic cancer ranks fourth [1,2]. Although in recent decades the 1-year survival rate has increased from 15% (1990) to 32% (2010), the 5-year survival rate remains very low at 5% without major changes [3].

The main reasons for the poor prognosis are the aggressive behavior of pancreatic cancers and the late onset of symptoms. Thus, for up to 85% of patients, a curative surgical treatment approach is no longer an option at diagnosis [4]. With a curative surgical approach, the 5-year survival rate increases to 20-30% [5].

Early detection

The earlier pancreatic cancer is detected, the higher the therapeutic success, which can increase to a 5-year survival rate of up to 50% if detected early and tumor biology is favorable [6].

In the absence of screening tests and early detection programs, it is important to identify potential symptoms early. The Swiss Pancreas Foundation publishes fact sheets (www.pankreasstiftung.ch) as part of an awareness program: Various symptoms (weight loss, reduction in general condition, nonspecific abdominal complaints, unexplained back pain, new-onset diabetes mellitus, icterus) should make one think of pancreatic cancer. Progress monitoring of radiological lesions, cysts, and inflammation of the pancreas also plays an important role.

Diagnostic procedure

According to a study from the USA in 2007, up to 40% of potentially operable patients were not offered surgical treatment [7], and adjuvant chemotherapy was also used too rarely [8]. Therefore, the clarification in specialized centers, which can also ensure the appropriate therapy and aftercare, is important. Figure 2 shows an overview of the procedure for suspected pancreatic cancer.

The gold standard for assessing resectability and staging is computed tomography of the thorax and abdomen [9]. Magnetic resonance imaging in combination with angio-MRI and MRCP (magnetic resonance cholangiopancreaticography) can help differentiate cystic pancreatic tumors and questionable liver metastases. Sonography may confirm bile duct obstruction, but assessability of the organ is often limited. Especially in the case of small tumors, endosonography can decisively complement other imaging methods.

Endoscopic retrograde cholangiopancreaticography (ERCP) has lost its value as a diagnostic test; therapeutically (stenting), ERCP is cardinal for the treatment of jaundice and cholangitis. However, the indication for preoperative biliary drainage should be individualized because of an increase in perioperative septic complications [10]. Routine biopsy before resection is still not recommended. However, endosonographically guided fine-needle biopsy can be used to confirm the diagnosis, for example, prior to palliative or even neoadjuvant chemotherapy. If peritoneal carcinomatosis is suspected (ascites, very high CA 19-9 level) or liver metastases, staging can be supplemented with diagnostic laparoscopy.

Tumor markers (CA 19-9, CEA, and NSE) may be helpful in combination with history, clinic, and radiologic examination. CA 19-9 has the highest sensitivity (80%) with a specificity of 75% for carcinoma. It should be noted that CA 19-9 may also increase in the setting of cholestasis. In patients with negative Lewis blood group antigens A and B (5-7% of the population), CA 19-9 is not expressed.

Therapy

In the majority of pancreatic cancer patients, distant metastasis or local infiltration of such a nature exists at the time of diagnosis that only a palliative therapy concept can be considered. Localized tumors can be approached curatively, sometimes with vascular infiltration.

Locally advanced pancreatic cancer should be discussed in an interdisciplinary manner regarding multimodality therapy. In each case, a balance is made between primary resection and neoadjuvant pretreatment (Fig. 2) [11].

Curative treatment

Surgical therapy remains the only curative option. Both surgical and oncologic outcomes of pancreatic procedures depend on a center’s “case load” [12]. Perioperative mortality is 2-4% and morbidity is approximately 40% in reference centers [13]. The main postoperative problems are fistulas (5-12%), bile leaks (2-6%), and delayed gastric emptying with difficult food buildup (15-20%). Relaparotomy is required in approximately 5% of cases.

Previously, tumors with vascular infiltration were considered inoperable. Today, venous resection (portal vein or superior mesenteric vein) is possible at specialized centers without increasing the complication rate [14,15]. Increasingly, arterial resections are also being performed, although the potential benefit should be discussed on a case-by-case basis [15,16].

Because complete tumor removal (R0 resection) and negative lymph node involvement are important prognostic factors, complete tumor removal with standard lymphadenectomy is the goal [17].

For tumors in the pancreatic head, a partial duodeno-pancreatectomy according to Whipple is performed, which can be performed either classically, taking the distal stomach with it, or pylorus-preserving (Fig. 3). Distal pancreatic carcinomas are operated on via en bloc resection of the pancreatic tail, taking the spleen with it. For locally advanced pancreatic cancer, total pancreatectomy is an option [15].

Chemotherapy

Neoadjuvant treatment: it is not yet clear whether preoperative chemotherapy (neoadjuvant therapy) confers a benefit in operable patients compared with primary surgery followed by chemotherapy (adjuvant treatment) [18]. Several phase III trials are currently underway and are expected to provide new insights into the use of neoadjuvant treatment. The NEOPA trial compared primary surgery vs neoadjuvant radiochemotherapy (gemcitabine, 50.4 Gy) [19]. The PREPANC study extends this question to borderline resectable tumors [20]. The NEOPAC trial compared adjuvant treatment (gemcitabine) vs neoadjuvant (gemcitabine plus oxaliplatin) followed by adjuvant (gemcitabine) treatment [21]. The ESPAC-5F trial compared four different approaches: Initial surgery, neoadjuvant radiochemotherapy (capecitabine, 50.4 Gy), neoadjuvant chemotherapy with gemcitabine, and neoadjuvant chemotherapy with folfirinox [22].

Adjuvant treatment: adjuvant chemotherapy is generally recommended postoperatively, as it has been shown to increase 5-year survival from 10% to 28% [23]. Nevertheless, the successes of adjuvant chemotherapy are still evolving. According to a randomized prospective multicenter European study (ESPAC-4), adjuvant combination therapy with gemcitabine and capecitabine resulted in a prolongation of survival by 2.5 months compared to treatment with gemcitabine alone (median 28 vs. 25.5 months) [24].

The development of individualized strategies for chemotherapy is an important area of future research. For example, bacterial colonization of pancreatic tumors has been shown to correlate with decreased response to gemcitabine [25]. In addition, immunological and genetic markers are increasingly correlated with survival and response to chemotherapy to enable individualized tailored treatment.

Palliative therapy

In locally advanced initially unresectable tumors, resectability was achieved in 61% and 46% of cases, respectively, during restaging after the use of folfirinox or radiation with gemcitabine [26]. Since the response to palliative resp. neoadjuvant therapy is not always radiologically clear, surgical exploration has a high diagnostic and therapeutic value in this situation (Fig. 2) [27].

In primary metastatic pancreatic cancer, the side-effect-intensive combination treatment of the folfirinox regimen showed the best results with a median survival of ten months [28]. The PRODIGE 4/ACCORD 11 trial demonstrated a survival benefit for folfirinox (median 11.1 months) over gemcitabine (6.8 months) in patients with metastatic pancreatic cancer [29]. Subsequently, the MPACT trial demonstrated a survival benefit for nab-paclitaxel-gemcitabine (median 8.7 months) over gemcitabine (6.6 months) in patients with metastatic pancreatic cancer [30]. Thus, depending on the general condition and tolerance of the patient, individualized palliative therapy can be offered.

In addition, there is increasing evidence that patients who have received palliative first-line chemotherapy benefit from second-line treatment with a different chemotherapeutic agent [31].

Whether the above treatment regimens in the palliative setting (with or without radiation) also qualify for treatment of patients without distant metastases (downstaging) is part of the current NEOLAP study (NCT02125136).

Mechanical problems such as bile duct or duodenal stenosis can be relieved endoscopically and/or surgically (palliative surgical “double bypass”, Fig. 3). Various other local interventions such as radiofrequency ablation and stereotactic body irradiation have not yet been established [32,33].

Aftercare

The American Society of Clinical Oncology noted in 2017 that for potentially cured pancreatic cancer patients, there is only moderate evidence for frequency, length, and content (imaging) of follow-up visits [34]. Other important aspects such as nutrition, psychology, pain management in advanced stages and others remain even less studied.

At our center, we care for patients with pancreatic cancer as part of an interprofessional pancreatic consultation. Diagnostic, therapeutic, medical and other measures are thus coordinated in a patient-centered manner between the professional groups involved (internist, surgeon, radiologist, nutritionist, psychologist and others). To capture as many aspects of the patient’s individual suffering and support needs as possible, we document quality of life and other information (such as nutritional status) prior to any intervention and continue care post-intervention. We recommend a lifetime connection. We limit the following section to aspects of nutrition and endocrine and exocrine organ insufficiency.

Malnutrition

Malnutrition in the setting of pancreatic tumor treatment is a key problem that negatively affects patient survival and cure rates [34]. Lack of hunger pangs, gastric emptying disorder, malabsorption, maldigestion, exocrine pancreatic insufficiency, side effects of (neo-)adjuvant therapy, and tumor recurrence or progression contribute to patient malnutrition [35].

Exocrine pancreatic insufficiency

Peroral enzyme substitution should be performed initially in all patients. One should start with 2000 lipase units per gram of dietary fat and gradually increase the dose to a maximum of 15 000-20 000 lipase units per kg of body weight if symptoms persist. Individual counseling is very important here, as the use of proton pump inhibitors is common, but these in turn interact with the efficacy of pancreatic enzyme substitution (acid-protected preparation of Creon®).

Vitamin deficiency

Causes of a deficit of fat-soluble vitamins may include alcohol consumption, marked exocrine insufficiency, and/or severely restricted fat intake [36]. To prevent deficiencies, regular monitoring of vitamin levels (vitamin D, B12, B6, β-carotene, folic acid), trace elements (zinc, manganese, etc.) and coagulation, and appropriate substitution are recommended.

Endocrine pancreatic insufficiency

Postoperatively, pancreopriver diabetes mellitus may develop. This may also be delayed, so HbA1c follow-up is initially indicated every three to six months.

Take-Home Messages

• Pancreatic cancer is the fourth most common tumor-associated cause of death, with an upward trend.
• Interprofessional care with individually differentiated therapy maximizes outcome: surgical resection remains the only chance of cure at the moment, but downstaging with reevaluation in borderline resectable tumors is a promising approach.
• Chemotherapeutic strategies are under development in both curative and palliative approaches, and the results of ongoing trials must be awaited.

Literature:

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Further reading:

• Marotta F, et al: Fat-soluble vitamin concentration in chronic alcohol-induced pancreatitis. Relationship with steatorrhea. Dig Dis Sci 1994; 39: 993-998.

InFo ONCOLOGY & HEMATOLOGY 2018; 6(3): 22-28.