Background
Pancreatic cancer is the fourth-leading cause of cancer-related deaths in the United States [
1] and is expected to become the second most common cancer by 2030 [
2]. Patients presenting with pancreatic cancer typically have a poor prognosis, because of the advanced stage of the disease at the time of diagnosis. Pancreatic cancer is associated with a very high mortality rate [
3]; an overall 5-year survival rate of 7% after diagnosis was reported over the 2004–2010 period [
1]. This survival rate was further reduced to 2% for patients with advanced disease [
1].
In patients with early-stage, resectable disease (15–20% of patients at time of diagnosis [
4]), surgical resection of the tumor can be performed and, although associated with a low success rate, it represents the only potentially curative intervention. Median survival for resected patients is in the region of 14–20 months [
5]. Five-year survival rates of up to 25% have been reported following pancreatectomy for ductal adenocarcinoma of the pancreas [
5‐
8]; however, these values have been questioned and actual rates are believed to be much lower [
9‐
12].
Approximately 80% of patients with pancreatic cancer present with either locally advanced or metastatic disease at time of diagnosis and are not suitable for surgery. Median survival for these patients is shorter (8–12 months for unresectable disease [
13] and less than 6 months for metastatic disease [
3,
10]).
Despite extensive research efforts over the last two decades, palliative treatment (e.g., chemotherapy and radiotherapy) has not significantly improved survival [
14], quality of life and tumor progression for patients with unresectable pancreatic cancer. In recent years, however, the clinical relevance of malnutrition caused by pancreatic exocrine insufficiency (PEI) both in resected patients and in patients with advanced, unresectable pancreatic cancer, has been investigated to improve supportive care [
15‐
17].
Malnutrition and significant weight loss are frequently observed in patients with pancreatic cancer [
18] and influence survival, resection rate, tumor progression, and quality of life [
5,
19]. Improvement of the nutritional status by parenteral nutrition enhances quality of life, and allows for tumor therapy to be administrated without interruption [
20].
While malnutrition and weight loss may be partly attributed to anorexia, diarrhea, early satiety [
21], chemotherapy, and/or tumor progression [
20], PEI may also be a determinant, either due to postoperative changes in the digestion process after tumor resection, or to the tumor itself obstructing the pancreatic duct [
22‐
24]. PEI causes digestion to be impaired, which commonly manifests as diarrhea and steatorrhea [
25]. Reduced digestion results in malabsorption of nutrients, leading to malnourishment [
18,
25]. A markedly reduced exocrine pancreatic secretion, as measured by low fecal elastase-1 (FE-1) levels, has been reported as an independent factor associated with poor prognosis in patients with advanced pancreatic cancer [
26]. In this patient population, partial pancreatic resection for pancreatic malignancy leads to sustained PEI and reduced quality of life [
27].
Oral pancreatic enzyme replacement therapy (PERT) is the standard treatment for PEI [
21,
23]. Patients with advanced pancreatic cancer who received PERT have shown significant weight gain after PERT [
16]. In addition, PERT was associated with significant improvement in fat and protein digestion in patients with a partial/total pancreatic resection [
28]. Of note, a recent study reported low rates of PERT prescription (21%) in patients with metastatic pancreatic cancer, in which the vast majority of patients had tumors of the pancreatic head and were likely to have had a blocked pancreatic duct [
29].
It is unclear whether treatment of PEI with PERT improves the survival of patients with either resectable or unresectable pancreatic cancer. Therefore, the aim of this analysis was to evaluate the impact of PEI diagnosis and treatment on the survival of patients with unresectable pancreatic cancer.
Discussion
This retrospective analysis conducted in patients with unresectable pancreatic cancer (locally advanced or metastatic disease) showed that the evaluation and treatment of PEI, in addition to standard chemotherapy and best supportive care, was associated with significantly prolonged survival compared with standard chemotherapy alone (189 versus 95 days, respectively, P < 0.001). This is especially true for patients with significant weight loss of more than 10% of their bodyweight at diagnosis. Palliative chemotherapy and PERT were independently associated with longer survival.
The incidence of pancreatic cancer is projected to increase to become the second most common cancer by 2030 [
2], yet the overall survival rate remains low [
1]. Around 80% of patients present with unresectable, advanced disease, which has a median survival of just 6–12 months [
4,
13]. Therefore, for this patient population, in which curative surgery is not possible, palliative and supportive care is key to prolonging survival and improving quality of life.
Cachexia can directly reduce the quality of life of patients with cancer, and pancreatic cancer often causes a high prevalence of severe cachexia [
32]. Cachexia has previously been shown to be associated with short survival and poor quality of life in patients with pancreatic cancer [
5,
19]. Furthermore, tolerance to chemotherapy is reduced in patients with cachexia and malnutrition [
33].
In patients with pancreatic cancer, weight loss is obviously multifactorial, but PEI plays a major role [
5,
34]. PEI can develop after surgery or may be caused by the tumor obstructing the pancreatic duct [
22,
24]. PEI, the presence of metastases, anemia, and hypoalbuminemia are all independent predictors of survival in patients with advanced pancreatic cancer [
26]. Furthermore, PEI has been shown to negatively impact the quality of life of patients with pancreatic cancer, mainly due to its associated difficulties in managing diet and gastrointestinal symptoms [
35]. The positive impact of PERT on survival reported in the present study in patients with unresectable pancreatic cancer and associated significant weight loss supports the relevant role of PEI in these patients. Conversely, PERT may have no benefit in patients with no significant weight loss.
Pancreatic enzyme replacement therapy, the standard treatment for PEI [
23], has been shown to improve weight gain in patients with advanced pancreatic cancer by improving digestion and nutrient absorption [
16]. This analysis shows that these improvements are reflected in improved survival rates in patients with unresectable pancreatic cancer who received PERT for PEI, together with standard oncologic therapy, compared with those who received oncologic therapy alone. Interestingly, the rate of survival of patients with PEI can be increased to the level of patients without PEI by giving PERT; this suggests that the enzyme doses used in this study (starting at 200000 Ph.Eur. per day, followed by titration up to a median dose of 325,000 Ph.U. per day according to body weight, symptoms, and nutritional status during follow-up) are effective in treating PEI in these patients. It should be underlined that PERT is well tolerated with mild and infrequent side effects [
36], which is especially important for patients with pancreatic cancer. In this analysis, no patient discontinued PERT due to side effects or intolerance.
In the present study, omeprazole was consistently administered to patients with PEI to improve the efficacy of PERT due to the resultant inhibition of gastric acid secretion. It is well known that PEI is not only the consequence of reduced pancreatic secretion of enzymes, but also of reduced bicarbonate secretion [
37]. Pancreatic enzymes in enteric-coated preparations require a pH higher than 5.5 for them to be released [
38]. Intestinal pH is frequently acidic in patients with PEI, thus avoiding the release of exogenous enzymes within the proximal gut [
39]. Addition of a proton pump inhibitor to PERT has been shown to be effective in improving fat digestion in patients with PEI [
40]. This is especially important in patients with unresectable pancreatic cancer in whom pancreatic secretion is markedly reduced due to the obstruction of the main pancreatic duct.
Palliative chemotherapy was strongly associated with a longer survival in this study. Nevertheless, only patients who were clinically judged to be suitable for chemotherapy were administered this treatment, whereas those who were unsuitable with a poor performance status were not administered chemotherapy. Thus, there is a very relevant bias in the selection of patients for chemotherapy, and it is not appropriate to use this study to evaluate the efficacy of this form of therapy. Interestingly, the proportion of patients in this study that were suitable for chemotherapy and the number of therapy cycles that these patients tolerated increased with PERT, thus suggesting that PERT may increase tolerance to chemotherapy.
The retrospective study design is the main limitation of the present study; however, the analysis was limited to hard objective variables that are well-recorded in clinical practice. In addition, this study used data from a single central electronic medical record of mandatory use for all the physicians in hospitals and health centers in the north-west region of Spain. This electronic medical record includes information on any medical assistance, as well as any laboratory tests, imaging, and any other examination performed. The use of this central electronic medical record markedly reduces the possibility of missed data. The limited number of patients included is also a limitation in this study, and is mainly due to the single-center study design and the need for pathological confirmation of pancreatic adenocarcinoma for inclusion. The single-center design limits the variability in patients’ care and therapy, and the requirement of pathological confirmation for inclusion avoids biases related to the inclusion of other malignant lesions. These two features could be therefore considered strengths of the study.
Prospective clinical trials are needed to confirm the impact of PERT in patients with unresectable pancreatic cancer, not only on survival, but also on their quality of life and tolerance to chemotherapy. A recent Phase II trial found that the mean percentage change in body weight of patients with unresectable pancreatic cancer did not differ significantly between those randomized to receive PERT or placebo for 8 weeks [
41]; however, this study had several limitations. The limitations included: a small sample size; short follow-up period; low enzyme dose (50,000 Ph.Eur. with main meal and 25,000 Ph.Eur. with snacks); tablets were used and not minimicrospheres; and finally, FE-1 levels were above the normal threshold of 200 μg/g stool in 44.1% of patients in the PERT group and 21.2% of those in the placebo group [
41]. Larger, well-designed, randomized trials are needed to identify patients who may benefit from PERT.
It is important to note that PERT is generally accepted for the treatment of PEI of any etiology, and until new data are available, it should be considered as part of the therapeutic armamentarium in patients with pancreatic cancer. This is important not only in clinical practice, but also in clinical trials for new chemotherapy agents. The possibility of PEI and its treatment with PERT in patients with pancreatic cancer has been consistently ignored in previous clinical trials of chemotherapy agents. The present study suggests that PERT increases tolerance to chemotherapy, and opens the question of whether the efficacy of standard chemotherapeutic agents could be improved by the inclusion of the evaluation and treatment of PEI with PERT as part of the best standard of care in these patients.