Efficacy of pancreatic exocrine replacement therapy for patients with unresectable pancreatic cancer in a randomized trial

Pancreatology 16 (2016) 1099e1105

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Original article

Efficacy of pancreatic exocrine replacement therapy for patients with unresectable pancreatic cancer in a randomized trial Sang Myung Woo a, *, Jungnam Joo b, So Young Kim c, Sang-Jae Park a, Sung-Sik Han a, Tae Hyun Kim a, Young Hwan Koh a, Seung Hyun Chung d, Yun-Hee Kim e, Hae Moon f, Eun Kyung Hong a, Woo Jin Lee a, * a

Center for Liver Cancer, National Cancer Center, Republic of Korea Cancer Biostatistics Branch, Research Institute for National Cancer Control and Evaluation, National Cancer Center, Republic of Korea Department of Clinical Nutrition, National Cancer Center, Republic of Korea d Rehabilitation Medicine, National Cancer Center, Republic of Korea e Molecular Imaging and Therapy Branch, Research Institute, National Cancer Center, Republic of Korea f Emergency Department, National Cancer Center, Republic of Korea b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 12 May 2016 Received in revised form 30 August 2016 Accepted 2 September 2016 Available online 4 September 2016

Background: Weight loss in pancreatic cancer is associated with maldigestion due to pancreatic duct obstruction. Pancreatic exocrine replacement therapy (PERT) may significantly improve fat and protein absorption. Objectives: This prospective, double-blind, randomized, placebo-controlled phase II trial assessed whether PERT could reduce or prevent weight loss in patients with unresectable pancreatic cancer. Methods: Sixty seven patients with unresectable pancreatic cancer were randomized to receive enteric coated PERT, consisting of 6e9 capsules of pancreatin (457.7 mg/capsule), or placebo. Patients took two capsules each three times daily during main meals and one capsule each up to three times daily when having between-meal snacks. The primary endpoint was the percentage change in body weight at eight weeks. Results: The mean percentage change in body weight (1.49% [1.12 kg] vs. 2.99% [1.63 kg], P ¼ 0.381) and the mean percent change in Patient-Generated Subjective Global Assessment (PG-SGA) score (8.85% vs. 15.69%, p ¼ 0.18) did not differ significantly between the PERT and placebo groups. There was no improvement in quality of life and overall survival did not differ significantly between the PERT and placebo groups (5.84 months vs 8.13 months, p ¼ 0.744). Conclusions: PERT did not reduce weight loss in patients with unresectable pancreatic cancer. Larger randomized trials are needed to identify those patients who may benefit from PERT. Trial registration: ClinicalTrials.gov Number NCT01587534. © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Keywords: Pancreatic cancer Pancreatic exocrine insufficiency Early palliative care Pancreatic exocrine replacement therapy

Introduction The prognosis of patients with pancreatic cancer is poor, with a five-year overall survival rate of less than 5%. Pancreatic cancer is the fifth leading cause of cancer deaths in Korea [1]. Most patients have locally unresectable or advanced metastatic disease at the time of diagnosis, and hence are eligible only for palliative

* Corresponding authors. Center for Liver Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, Republic of Korea. E-mail addresses: [email protected] (S.M. Woo), [email protected] (W.J. Lee). http://dx.doi.org/10.1016/j.pan.2016.09.001 1424-3903/© 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.

treatment options. Almost all patients with pancreatic carcinoma present with weight loss at the time of diagnosis, and this weight loss is progressive [2]. In addition, weight loss prior to chemotherapy was found to have a prognostic effect on survival in patients with several tumor types, including pancreatic cancer [3,4]. Most patients with pancreatic cancer have the impeded flow of pancreatic juice due to mechanical obstruction of the pancreatic duct. This may cause exocrine pancreatic insufficiency with fecal losses of energy through steatorrhea. Pancreatic exocrine replacement therapy (PERT) is standard therapy for fat and protein malabsorption [5]. Despite the high incidence of pancreatic exocrine insufficiency (PEI) in patients with pancreatic cancer, the

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treatment of these patients is often restricted to the oncological aspect whereas PEI is frequently disregarded. Few studies to date have investigated the incidence of exocrine insufficiency in patients with pancreatic cancer, and those studies have yielded inconsistent results. The incidence of PEI in patients with unresectable pancreatic cancer was shown to be 87% using secretin tests [6] and 68% using stool elastase tests [7]. Among patients with pancreatic cancer undergoing surgery, the incidence of exocrine insufficiency was 92% before surgery [8]. The high rates of exocrine insufficiency in pancreatic cancer patients support the use of PERT in this patient group. Few studies to date have analyzed the effects of PERT in patients with pancreatic cancer and there is no clear guide to identify those patients who benefit from PERT [9e11]. In only one double-blind, randomized control trial, 21 patients with unresectable cancer of the pancreatic head were randomized to PERT or placebo [12]. Patients in the PERT group were given 50,000 units of lipase with meals and 25,000 units of lipase with snacks. Compared with controls, the subjects receiving PERT experienced a 12% increase in fat malabsorption and a 1.2% increase in body weight. This prospective, randomized, placebo-controlled trial therefore assessed the ability of PERT, combined with dietary counseling, to reduce or prevent weight loss in patients with unresectable pancreatic cancer. Methods Patients All patients enrolled in this single center, double blind, randomized phase II trial provided written informed consent, and the study protocol was approved by the institutional review board of the National Cancer Center of Korea. Patients were considered eligible for inclusion if they had unresectable pancreatic cancer, proven by cytology or histology; local unresectability, or advanced disease with metastases; were aged over 18 years; had ECOG scale of performance status (0-3); and agreed to record daily food intake. Tumor of pancreas head or body/tail location was not preferred for enrolment. Subjects were excluded if they had a history of major gastrointestinal surgery, chronic gastrointestinal disease (e.g., Crohn's disease), decompensated diabetes, or diabetes mellitus with severe gastroparesis. Gastroparesis was suspected in patients with nausea, vomiting, early satiety, postprandial fullness, abdominal pain, or bloating. A mechanical obstruction was excluded with or upper endoscopy; if pancreatic pseudocysts impeding gastric or duodenal passage were present; if they were being treated with antacids, mucosal protective agents, H 2receptor antagonists, or proton pump inhibitors that could not be discontinued; if they were taking concomitant medications affecting gastroduodenal motility (e.g. metoclopramide and erythromycin), or interfering with bile secretion (e.g. bile acids); if they had abused alcohol during the three months preceding the study, had a known allergy to pancreatin, had undergone any major surgery within 4 weeks prior to study treatment, or were pregnant or lactating. Patients were randomized to PERT or placebo using unique patient numbers, with treatment started within seven days of date. Randomization was stratified based on extent of disease (locally advanced vs. metastatic). Treatment PERT consisted of Norzyme® (Nordmark Arzneimittel GmbH & Co. KG, Germany), a high dose enteric coated pancreatic enzyme preparation. Each tablet contained 25,000 European

Pharmacopoeia (Ph. Eur.) units of lipase, 22,500 Ph. Eur. units of amylase, and 1250 Ph. Eur. units of protease. Patients took two capsules each three times daily during main meals and one capsule each up to three times daily during between meal snacks (total, 6e9 capsules/day) for eight weeks. The placebo matched the active drug in appearance, taste, and weight and contained pharmacologically inactive substances. Using preprinted diaries, patients recorded their daily dietary intake over three consecutive days and randomized one week later. There were no strict rules or prohibitions with respect to dietary intake. After the eight-week double blind trial period, patients were followed for an additional 16 weeks in an open descriptive trial period; during this time, patients were recommended to take PERT. The daily intake of energy and nutrients were calculated using the CAN-pro 3.0 (Korean Nutrition Society, Korea). Follow-up Follow up visits were scheduled every four weeks until 12 weeks after the randomization visit. During each visit, body weight, ECOG performance status, and vital signs were measured. At 8 weeks, dietary and nutrition status (Patient-Generated Subjective Global Assessment, PG-SGA) [13] and stool elastase-1 activity were measured. Patients were also evaluated by stool fat-Sudan III staining and on the EORTC QLQ-C30 General Questionnaire, Korean version. PG-SGA score is a continuous measure [14]. Scores of 0e4 were assigned to each component of the PG-SGA score, depending on the impact of that symptom on nutritional status; the total score consists of a sum of the component scores. A higher score is associated with a greater risk for malnutrition. Pancreatic exocrine function was evaluated clinically. The occurrence and severity of complaints and symptoms associated with abdominal cramp and dyspepsia were assessed using a questionnaire. Patients were also questioned about potential side effects of treatment. Statistical analysis The primary goal of the trial was to investigate the percentage change in body weight eight weeks after randomization. The secondary goals were to estimate change in PG-SGA score; daily dietary intake of total calories, fat, protein, and carbohydrates; frequency of abdominal pain daily, frequency of flatulence, change in QOL score, and overall survival. The sample size calculation was based on the primary endpoint, percentage change in body weight eight weeks after randomization [12]. In the previous study [12], the mean (SD) percentage change in body weight was 3.7 (4.4) % with 95% CI (4.56%, 2.84%) in a placebo group, and 1.2 (4.3)% with 95% CI (0.36%, 2.04%) in an enzyme group. Thus, the estimated mean difference in percentage change in body weight between two treatment groups was 4.9%. However, considering the small sample size of the study, a conservative estimate of the mean difference in percentage change in body weight was calculated using the difference between the upper 95% CI of the placebo group and lower 95% CI of the enzyme group. This conservative estimate was 3.2% (0.36%, 2.84%), and the current study was powered to detect this difference. Using a two-sided t-test with a type I error rate of 5%, sample size of 30 subjects per group can detect this difference with 80% power. Estimating a dropout rate of 10%, Estimating a drop-out rate of 10%, a 33 and 34 patients were required. It was planned to recruit patients over a 24 month period. The primary statistical analysis was performed for on the intent-to-treat (ITT) population. The frequency and rates of categories were determined for nominal variables and ordered

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variables in each group. Mean and standard deviation were calculated for continuous variables. Chi-square tests or Fisher's exact test, and t-tests or Wilcoxon rank sum test as appropriate were used to compare nominal and continuous variables, respectively, with significance defined as a two-sided p value < 0.05. Results Baseline characteristics of patients Between September 1, 2011, and December 31, 2014, 75 patients with unresectable pancreatic cancer were enrolled and 67 were randomized to receive enteric coated PERT or placebo (participation rate, 88.1%; Fig. 1). Table 1 summarizes the patients' characteristics. The groups were balanced on important prognostic factors (p > 0.05 each) (Table 1). Of the included patients, 43% had severe PEI (stool elastase-1 < 100 mg/g) and 24% had moderate PEI (stool elastase-1100e200 mg/g), but only 4% were positive on fat-Sudan III staining. There was no significant difference between two groups. Twenty-three patients (34%) had tumors located in the pancreatic head. Endoscopic ultrasonography guided fine needle aspiration provided a cytologic diagnosis in 31 (46%) patients and others were diagnosed by histology using percutaneous needle biopsy [liver, n ¼ 23 (34%); pancreas, n ¼ 6 (9%); lymph node, n ¼ 3 (4%); abdominal wall n ¼ 1(1%)]; or endoscopic forceps [bile duct, n ¼ 3 (4%)]. The average time interval from pathologic diagnosis of pancreatic cancer and enrolment into the study was only 1 day. (0e7 days, n ¼ 59; 8e14 days, n ¼ 5; 15e31 days; n ¼ 3). Efficacy and safety of PERT During the double blind trial period, three patients died, one in the PERT group and two in the control group. Medication compliance during this period was comparable in the two groups; median intake was 5.9 capsules/day (range: 0.9e10.3 capsules/day) in the

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placebo group and 6.1 capsules/day (range: 1.9e9.1 capsules/day) in the PERT group. Intent-to-treat analysis showed no significant difference in the percentage change in body weight at 8 weeks in the PERT and placebo groups (Table 2). Patients in the PERT group lost 1.49% (1.12 kg) body weight, whereas patients in the placebo group lost 2.99% (1.63 kg) (p ¼ 0.381). Per protocol analysis showed that changes in days per week with steatorrhea, daily total calorie intake, and PG-SGA did not differ significantly between the two groups (Table 3). Of 67, 62 eligible patients (93%) completed the questionnaire at 8 weeks., with no between group difference in improvements in QOL scores (Table 4). No serious PERT-related adverse events were reported. Subgroup analyses according to tumor location showed that, in patients with unresectable cancer of pancreatic head region, the percent change of PG-SGA score was 42.65% in the PERT group and 32.93% in the placebo group (p ¼ 0.039) (Table 5, Fig. 2). Open descriptive trial period Overall survival did not differ significantly between the PERT and placebo groups (5.84 months vs 8.13 months, p ¼ 0.744). Twenty-one patients died and seven discontinued the trial during the terminal phase of their illness. Twenty-nine patients completed the open descriptive trial period, 15 in the PERT group and 14 in the placebo group. Four patients randomized to PERT during the double blind trial period were switched to a dose of one capsule three times per day during main meals. In contrast, 10 patients were switched from placebo to PERT, at a dose of one capsule three times per day. Discussion Systemic chemotherapy is frequently the primary mode of treatment for patients with advanced/metastatic pancreatic cancer.

Fig. 1. CONSORT diagram: patient recruitment, treatment, and analysis.

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Table 1 Baseline patient characteristics. Characteristics

PERT (n ¼ 34)

Placebo (n ¼ 33)

P-value

Age, yr, mean ± SD Sex (male), n (%) ECOG, n (%) 1 2 3 Height, cm, mean ± SD Weight, kg, mean ± SD BMI, mean ± SD Blood chemistry, mean ± SD Albumin (g/dL) Total bilirubin (mg/dL) Alkaline phosphatase (IU/L) AST (IU/L) ALT (IU/L) Tumor marker, median (range) CA19-9 (U/ml) Stool test Elastase-1, n. (%) 200 mg/g 100e200 mg/g <100 mg/g Fat-Sudan III stain, n (%) Positive Negative Location of tumor, n (%) Head Tail & body Extent of disease, n (%) Locally Advanced Metastatic 1st line treatment, n (%) FOLFIRINOXb Gemcitabine plus cisplatin Gemcitabine plus erlotinib Gemcitabine Radiation therapy None

63.7 ± 9.7 22 (64.7)

64.1 ± 10.6 21 (63.6)

0.75a 0.93 1

1 (2.9) 32 (94.1) 1 (2.9) 161.2 ± 8.0 58.7 ± 10.8 16.1 ± 13.5

1 (3.0) 31 (93.9) 1 (3.0) 161.9 ± 9.9 56.1 ± 8.3 13.3 ± 6.9

0.48a 0.28a 0.91a

4.4 ± 0.5 1.4 ± 1.8 186.5 ± 170.2 38.7 ± 32.9 43.5 ± 42.0

4.3 ± 0.3 1.8 ± 3.0 203.9 ± 195.7 46.0 ± 84.8 62.0 ± 140.6

0.2 0.79a 0.78a 0.62a 0.67a

655.5 (2.0, 1012037.0)

Placebo 372.5 (2.0, 75921.0)

0.23a

15 (44.1) 7 (20.6) 12 (35.3)

7 (21.2) 9 (27.3) 17 (51.5)

2 (6.3) 30 (93.8)

1 (3.7) 26 (96.3)

12 (35.3) 22 (64.7)

11 (33.3) 22 (66.7)

9 (26.5) 25 (73.5)

9 (27.3) 24 (72.7)

4 (11.8) 8 (23.5) 15 (44.1) 2 (5.9) 2 (5.9) 3 (8.8)

4 (12.1) 6 (18.2) 16 (48.5) 4 (12.1) 3 (9.1) 0

a b

0.13

1

0.13

0.94

0.76

Wilcoxon rank sum test. FOLFIRINOX: The regimen includes the drugs fluorouracil (also known as 5-FU), leucovorin, irinotecan, and oxaliplatin.

Table 2 Primary end points at 8 week (ITT set). Parameters (SD)

PEST (n ¼ 34)

Placebo (n ¼ 33)

P-value

Change in body weight (%) Change in body weight (kg)

1.49 (7.23) 1.12 (4.80)

2.99 (5.97) 1.63 (3.18)

0.614 0.381

However, the benefits of chemotherapy versus supportive care in some patients with advanced pancreatic cancer and borderline/ poor performance status are unclear. A trial in patients with lung cancer showed that early palliative care intervention plus standard treatment improved QOL and overall survival compared with standard treatment alone [15]. However, the specific components

of the palliative care provided were incompletely defined, and few publications have quantified how supportive care is defined within clinical studies [16]. Reduced exocrine pancreatic secretion is an important consequence of pancreatic cancer and its incidence is high among patients with advanced disease. One previous study reported that one-quarter of these patients had extremely severe pancreatic exocrine impairment, which was strongly associated with poor survival [17]. Effective management protocols are needed, including PEI assessment and improved diagnostic criteria, to explore the relationship between PEI and reduced morbidity in patients with pancreatic cancer [18]. This study found that PERT improved PG-SGA scores in patients with advanced pancreatic cancer in the head of the pancreas. These

Table 3 Secondary end points at 8 week (per protocol set). Parameters (SD) a

Change in PG-SGA % Change in PG-SGAa Daily total caloric intake Daily fat intake (g) Daily protein intake (g) Daily carbohydrate intake (g) Days with abdominal cramps per week Occurrence of flatulence a

Wilcoxon rank sum test.

PEST (n ¼ 32)

Placebo (n ¼ 30)

P-value

Missing value (PEST/Placebo)

2.48 (6.92) 8.85 (127.56) 1487.5 (655.2) 31.26 (19.65) 56.72 (26.30) 248.6 (103.8) 3.03 (3.46) 16 (53.33)

0.25 (5.57) 15.69 (71.7) 1297.7 (552.8) 29.44 (18.89) 53.85 (25.23) 208.8 (88.74) 3.50 (3.05) 13 (50.0)

0.16 0.18a 0.29 0.16 0.70 0.83a 0.3947a 0.80

17 (7/10) 14 (8/6)

9 (6/3) 6 (2/4)

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Table 4 QOL transformed scores.a Parameters (SD)

PEST (n ¼ 32)

Placebo (n ¼ 30)

P-valueb

Global health status Functional scale Physical Role Emotional Cognitive Social Symptom scale Fatigue Nausea and vomiting Pain Dyspnea Insomnia Appetite loss Constipation Diarrhoea Financial difficulties

51.39 70.16 66.89 66.11 71.11 78.33 68.33 31.11 51.11 15.00 33.89 28.89 27.78 38.89 25.56 21.11 37.78

42.63 63.23 59.74 56.41 69.87 71.15 58.97 35.78 55.98 22.44 38.46 25.64 30.77 57.69 24.36 24.36 42.31

0.16 0.19 0.36 0.26 0.70 0.20 0.31 0.47 0.51 0.52 0.49 0.71 0.57 0.05 0.70 0.52 0.59

a b

(21.23) (24.58) (25.10) (32.31) (29.42) (29.41) (24.51) (19.70) (32.31) (27.10) (32.31) (34.72) (36318) (35.11) (31.18) (33.31) (27.31)

(24.30) (24.76) (27.16) (33.02) (26.88) (29.65) (27.58) (31.11) (26.38) (32.64) (32.58) (34.39) (32.56) (35.97) (34.71) (32.05) (27.58)

Missing values (Nozyme/Placebo): 6(4/2). Wilcoxon rank sum test.

results suggest that PERT may be an important component of early palliative intervention in patients with unresectable cancer of the pancreatic head. This finding may be limited by the fact that it was only a post-hoc analysis and the sample size was small i.e. only 22 patients. PEI was shown to be present in 50e100% of in patients with unresectable pancreatic cancer [2,17,19]. Stool elastase-1 levels were found to be lower in many patients with pancreatic head cancer, jaundice, and clinical steatorrhea [2,17]. A prospective evaluation based on stool elastase-1 levels found that 67% of 32 patients with unresectable cancer of the pancreatic head had PEI at diagnosis and 89% had PEI at the 2-month follow-up [19,20]. Of the 67 patients in the present study, 45 (56%) had exocrine insufficiency at the time of diagnosis, as shown by stool elastase-1 concentrations. These concentrations, however, did not differ by tumor location. Among all patients enrolled into the present study, 23 patients presented with jaundice. Among 23 patients, 18 had cancer of pancreas head, 5 patients had cancer of pancreas body or tail. The biliary metal stents were inserted in these patients with unresectable or metastatic pancreatic cancer since they provide rapid and long term relief from the jaundice. Therefore, the effect of jaundice lasted for short period i.e. <2 weeks. The effect of jaundice contributed only minimally to the clinical outcome. Patients were excluded from the study if they were being treated with H 2-receptor antagonists or proton pump inhibitors that could not be discontinued. We used an enteric coated pancreatic enzyme to avoid inactivation in the stomach, as the enzyme is protected from the acidic environment by the coating. However, effective delivery and release are difficult to achieve because the pH in the stomach can fluctuate from 6, owing to the buffering capacity of the meal, down to 2 during the fed state, and the duodenal pH ranges from 4 to 6, with high individual variability. In an effort to reduce the variability, we excluded patients taking

Fig. 2. Change in PG-SGA in patients with unresectable pancreatic head cancer.

H2-receptor blockers or proton pump inhibitors. The pancreas has a large functional reserve, with clinically evident PEI occurring only when 90% of the function is lost and the secretion of pancreatic enzymes is less than 10% of normal [21]. Pancreatic atrophy secondary to tumor-induced pancreatic duct obstruction and pancreatic fibrosis can lead to PEI in patients with advanced pancreatic cancer [22]. However, more recent studies of patients with unresectable pancreatic cancer, including two trials with 12 and 194 patients, respectively, found no statistically significant correlation between subjective steatorrhea and fat malabsorption, as shown by stool testing [2,17]. Similar findings were observed postoperatively [23]. These results demonstrate a lack of correlation between symptoms and PEI. As most patients in the present study received active anticancer treatment, including chemotherapy and radiation therapy, many symptoms and QOL markers may be due to treatment response and adverse events. The secretion of pancreatic enzymes and bicarbonate is inversely correlated with the extension of pancreatic duct obstruction, resulting in manifest exocrine insufficiency when more than 60% of the pancreatic duct is blocked [12]. Pancreatic outflow obstruction was found to be more influenced by the length of longitudinal involvement of the main pancreatic duct than by the degree of its dilatation [24]. Although this study found that stool elastase-1 levels did not differ by tumor location, the effect of PERT

Table 5 Change in PG-SGA according to tumor location. Parameters (SD)

Head (n ¼ 22) Nozyme (n ¼ 11)

Placebo (n ¼ 11)

% Change in PG-SGA Change in PG-SGA

42.65 (37.33) 5.75 (6.63)

32.93 (87.62) 1.33 (6.71)

P-value

Tail & body (n ¼ 40) Nozyme (n ¼ 21)

Placebo (n ¼ 19)

0.039 0.045

33.09 (147.81) 0.94 (6.68)

1.58 (56.04) 0.64 (4.59)

P-value

0.7777 0.8960

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on PG-SGA score was observed only in patients with tumors of the pancreatic head. More than 20 tests have been developed for the assessment of pancreatic exocrine function, but few are clinically available. Although measurement of stool elastase-1 is currently preferred [25], this test shows a lower specificity for PEI impairment than direct tests. Stool elastase-1 testing may be limited to patients who will likely benefit from PERT. No specific product or delivery system has been shown superior in the treatment of fat malabsorption in patients with exocrine pancreatic insufficiency [5]. Pancreatic enzyme preparations have been used in several human diseases with a wide range of safety. To date, the only side effect that may be related to the use of pancreatic enzyme preparation was observed in children with cystic fibrosis. In these patients, mega doses of pancreatic enzymes (the equivalent of 10,000 U lipase per kg body weight per day) resulted in a distinctive form of fibrosing colonopathy [10,26]. However, none of the patients in the present study experienced any serious drugrelated adverse events. This study had several limitations. For example, fat absorption coefficients were not measured. These coefficients are considered the current standard for evaluating the efficacy of PERT products, although there is little evidence showing that the coefficient of fat absorption correlates with clinically relevant outcomes [27]. Many patients lacking measurable pancreatic enzyme activity are capable of absorbing up to 50 g of fat per day because of nonpancreatic sources of lipase [12]. This may lead to an overestimation of the fat absorption coefficient and to an underestimation of the efficacy PERT. In the present study, median daily fat intake was 31.26 g in the PERT group and 29.44 g in the placebo group. In addition, patients in the present study showed very low BMI at enrolment. Asian populations have in common is that, in general, the mean or median BMI is lower than that observed for non-Asian populations. Most patients with advanced pancreatic cancer present with weight loss. However, almost all patients (97%) included in the present study had good performance status (ECOG-PS 0-2). As shown in Table 1, distribution of 1st line treatment modalities was not different between two groups. There was no significant difference regarding best response to the diverse treatment modalities. Among 27 evaluable patients randomized to the PERT, 5 patients (19%) had a PR and 15 patients (56%) had a stable disease. Among 25 evaluable patients randomized to the placebo group, 4 patients (16%) had a PR and 11 patients (44%) had a stable disease. We cannot completely rule out the possibility as the confounding effect of chemotherapy on body weight. The possibility of confounding was believed to be low in the present study. In conclusion, this study found that PERT did not reduce weight loss in patients with unresectable pancreatic cancer. However, PERT may improve nutritional status in patients with unresectable cancer of the pancreatic head region. Larger randomized trials are required to assess the effects of PERT on weight loss in patients with pancreatic head cancer.

Acknowledgements I would like to thank wholeheartedly Boa Kim and Meeyoung Lee, the Reseach Coordinators, for timely processing the research environment and being so helpful in times of need. This study was partly sponsored by Pharmbio Korea Co., Ltd (1141310-1). The present study was partly supported by grants from the National Cancer Center, Korea (Grant numbers 1510202-2, 1610040-1).

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