Re: 췌장암 환자 72%가 췌장소화효소 외분비 장애.. 이럴때 소화효소 치료법 효과

[문형철]

췌장암 환자에서 췌장 소화 효소 보충제(이하 PERT: Pancreatic Enzyme Replacement Therapy)를 투여하면 복통이 줄고 식욕이 개선되는 기전은 주로 췌장 외분비 기능 부족(PEI: Pancreatic Exocrine Insufficiency)으로 인한 소화불량과 영양실조를 교정하는 데 기반합니다. 먼저 제공된 논문(PMC7724551)을 기반으로 설명한 후, 최근 연구들을 보완하여 자세히 풀어보겠습니다.

기본 기전 (PMC7724551 기반)

췌장암 환자,

특히 진행성 췌장암(APC)에서 PEI의 유병률은 약 72%로 높습니다.

이는 종양이 췌장 주관을 막거나 섬유화,

외분비 조직 손실로 인해

소화 효소(리파아제, 프로테아제, 아밀라아제)가 부족해지기 때문입니다.

결과적으로

지방, 단백질, 탄수화물의 소화와 흡수가 제대로 안 돼

스테아토레아(지방변), 영양실조, 체중 감소, 복부 팽만, 설사 등이 발생합니다.

이러한 증상은

식사 후 복통을 유발하고, 식욕을 떨어뜨려 환자가 식사를 피하게 만듭니다.

PERT는

돼지 췌장에서 추출한 효소를 장용 코팅으로 보충해 장내에서 방출되도록 합니다.

이는 지방 흡수 계수(CFA)를 개선하고, 영양 흡수를 촉진해 체중을 유지하거나 증가시킵니다(연구에서 PERT 그룹에서 8주 후 체중 3.27% 증가).

통증 감소 기전은

소화불량으로 인한 장내 가스 축적과 염증을 줄이는 데 있으며,

영양 상태 개선으로 전반적인 증상이 완화되어 식욕이 회복됩니다.

또한 생존 기간 연장(평균 3.78개월) 효과도 관찰됐습니다.

다만, 이 논문은 통증과 식욕에 대한 정량적 메타분석 데이터가 부족하다고 지적합니다.

최신 연구 보완 설명

최근 연구들(2022~2025)을 검색하고 분석한 결과, PERT의 기전은 여전히 PEI 교정에 초점을 맞추지만, 통증 완화와 식욕 개선에 대한 더 구체적인 메커니즘과 임상 증거가 보강됐습니다. 주요 포인트는 다음과 같습니다:

1. 통증 감소 기전:
   • 소화불량으로 인한 복부 불편(팽만, 경련)이 주요 원인입니다. PERT는 리파아제를 통해 지방을 글리세롤과 지방산으로 분해하고, 프로테아제를 통해 단백질을 펩타이드와 아미노산으로, 아밀라아제를 통해 전분을 덱스트린과 단당류로 분해합니다. 이는 장내 pH 5.5 이상에서 효소가 활성화되는 메커니즘으로, 소화 흡수를 정상화해 스테아토레아와 관련된 염증을 줄입니다.
   • 최근 리뷰에서 PERT가 식사 관련 복통을 완화한다고 보고됐습니다. 예를 들어, EPI 환자에서 PERT가 소화 증상을 개선해 활동 제한과 정서적 고통을 줄이고, 심지어 오피오이드(하이드로모르폰) 용량을 감소시켰다는 사례가 있습니다. 그러나 만성 췌장염(CP)에서 PERT가 복통 완화에 효과가 없다는 메타분석 결과가 있지만, 췌장암(PC)에서는 영양실조 관련 통증에 더 효과적일 수 있습니다.
   • 캐시시아(악액질) 관리 프로토콜 연구에서는 PERT를 캐시시아 예방/치료 intervention으로 포함, 종양 유래 인자와 사이토카인 증가로 인한 근육/지방 분해를 영양 흡수 개선으로 간접 완화한다고 제안합니다. 이는 통증(특히 영양실조 관련)을 줄이는 데 기여할 수 있습니다.
2. 식욕 개선과 식사 시작 기전:
   • PEI로 인한 영양실조(체중 감소 85%, 식욕부진 83%)가 식욕을 억제합니다. PERT는 지방 흡수율을 높여 체중 증가(예: 0.7kg 증가 vs. 대조군 2.2kg 감소)와 BMI 개선을 유발하며, 비타민 A/D/E/K 결핍을 방지합니다. 이는 전반적 웰빙을 높여 식욕을 회복시킵니다.
   • 최신 연구에서 PERT가 화학요법 내성을 높이고 생존율을 연장(301일 vs. 89일)한다고 하며, 이는 영양 상태 개선으로 식사 섭취를 촉진하는 데 기인합니다. 또한, 췌장 절제 후 PERT가 대변 빈도 감소와 생활의 질 향상을 보였습니다.
   • 전문가 의견에서는 PERT를 PEI 의심 시 경험적으로 처방할 것을 권고하며, 식사와 함께 복용(식사 중 반복 투여)으로 효과를 극대화합니다. 이는 증상(설사, 팽만) 감소로 환자가 식사를 시작하게 만듭니다. 다만, 준수율이 낮아(50%) 교육과 다학제 접근이 필요합니다.

전체적으로 PERT는 췌장암 환자의 증상을 직접적으로 교정하며, 최근 연구들은 영양-통증-식욕의 상호 연결성을 강조합니다.

United European Gastroenterol J

. 2020 Jul 6;8(9):1115–1125. doi: 10.1177/2050640620938987

Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: A systematic review and meta-analysis

Daniel de la Iglesia 1, Bartu Avci 2, Mariia Kiriukova 3, Nikola Panic 4,5, Maryana Bozhychko 6, Vasile Sandru 7, Enrique de-Madaria 6,✉, Gabriele Capurso 8

• Author information
• Article notes
• Copyright and License information

PMCID: PMC7724551  PMID: 32631175

Abstract

Background

Pancreatic cancer is the fourth leading cause of cancer mortality. Most patients are diagnosed with advanced pancreatic cancer, either at locally advanced or metastatic stages, and have a high rate of malnutrition and weight loss which are associated with poor outcomes. Pancreatic exocrine insufficiency is one of the causes of malnutrition and weight loss in these patients. The preval‎ence and clinical consequences of pancreatic exocrine insufficiency in advanced pancreatic cancer are poorly investigated with heterogeneous results. We sought to determine the preval‎ence and clinical consequences of pancreatic exocrine insufficiency and the effect of pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer by systematic review and meta-analysis.

Methods

Scopus, Medline, and Embase were searched for cohort studies or randomised clinical trials reporting pancreatic exocrine insufficiency and/or the effect of pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer. We considered pancreatic exocrine insufficiency as an abnormal result on direct and/or indirect pancreatic exocrine function tests. Pancreatic enzyme replacement therapy was eval‎uated by its effect on survival and quality of life in patients with advanced pancreatic cancer.

Results

A total of 11 studies were included; seven studies reported the preval‎ence of pancreatic exocrine insufficiency and seven the effect of pancreatic enzyme replacement therapy in advanced pancreatic cancer. The pooled preval‎ence of pancreatic exocrine insufficiency in advanced pancreatic cancer was 72% (95% confidence interval: 55–86%), being significantly higher when tumours were located in the pancreatic head (relative risk = 3.36, 1.07–10.54; p = 0.04) six studies investigated the impact of pancreatic enzyme replacement therapy on survival/quality of life. Pancreatic enzyme replacement therapy was associated with 3.8 months (95% confidence interval: 1.37–6.19) survival benefit. Patients receiving pancreatic enzyme replacement therapy had a trend towards a better quality of life.

Conclusions The preval‎ence of pancreatic exocrine insufficiency in advanced pancreatic cancer is substantial and its treatment can improve the outcomes of these patients.

배경

췌장암은 암 사망 원인 중 네 번째로 흔합니다. 대부분의 환자는 국소 진행성 또는 전이성 단계에서 진행성 췌장암으로 진단되며, 불량한 예후와 연관된 높은 영양실조 및 체중 감소율을 보입니다. 췌장 외분비 기능 부전은 이러한 환자에서 영양실조 및 체중 감소의 원인 중 하나입니다. 진행성 췌장암에서 외분비 기능 부전의 유병률과 임상적 결과는 제대로 연구되지 않았으며, 연구 결과도 이질적이다. 우리는 체계적 문헌고찰과 메타분석을 통해 진행성 췌장암 환자에서 외분비 기능 부전의 유병률과 임상적 결과, 그리고 췌장 효소 대체 요법의 효과를 규명하고자 하였다.

방법

Scopus, Medline, 및 Embase 데이터베이스를 검색하여 진행성 췌장암 환자에서 췌장 외분비 기능부전 및/또는 췌장 효소 대체 요법의 효과를 보고한 코호트 연구 또는 무작위 임상시험을 선정하였다. 췌장 외분비 기능부전은 직접적 및/또는 간접적 췌장 외분비 기능 검사에서 비정상적인 결과로 정의하였다. 췌장 효소 대체 요법의 효과는 진행성 췌장암 환자의 생존율 및 삶의 질에 미치는 영향으로 평가하였다.

결과

총 11건의 연구가 포함되었으며,

7건은 진행성 췌장암에서 췌장 외분비 기능 부전의 유병률을,

7건은 췌장 효소 대체 요법의 효과를 보고하였다.

진행성 췌장암에서 췌장 외분비 기능 부전의 통합 유병률은 72%(95% 신뢰구간: 55–86%)였으며,

종양이 췌장두부에 위치할 경우 유의하게 높았다(상대 위험도 = 3.36, 1.07–10.54; p = 0.04).

6건의 연구는 췌장 효소 대체 요법이

생존율/삶의 질에 미치는 영향을 조사했다.

췌장 효소 대체 요법은

3.8개월(95% 신뢰구간: 1.37–6.19)의 생존 이득과 연관되었다.

췌장 효소 대체 요법을 받은 환자들은 삶의 질이 개선되는 경향을 보였다.

결론

진행성 췌장암에서 외분비 췌장 기능 부전의 유병률은 상당하며,

그 치료는 해당 환자의 예후를 개선할 수 있다.

Keywords: Pancreatic cancer, exocrine pancreatic insufficiency, malnutrition, preval‎ence, survival

Introduction

Pancreatic cancer (PC) is the ninth most common cancer in Europe and the fourth leading cause of death from malignancy.1 PC has a very poor prognosis with only a 24% one-year survival rate and 9% at 5 years.2 Survival in PC is mainly influenced by stage at diagnosis; in patients with an early stage (around 10% at the diagnosis), surgical resection of the tumour can be performed with a 32% 5-years survival rate. However, approximately 80% of patients are diagnosed with locally advanced or metastatic disease with a five-year survival rate of only 1% and 3% respectively.3

Despite advances in chemotherapeutics, the five-year survival rate among patients with advanced PC (APC) has only marginally improved over the past 40 years.4 The reasons for this poor survival are multifactorial and include biological aggressiveness, diagnosis at advanced disease stage, and the fact that due to advanced age and comorbidities a large proportion of patients do not receive any treatment.5

The poor performance status of PC patients is also due to malnutrition. At presentation, 30% of patients are malnourished, 80% report weight loss, and over a third have lost more than 10% of their initial body weight.6 Anorexia and cachexia are frequent features of APC and reduce the patient’s ability to receive chemotherapy and influence survival and quality of life.7 Improving the nutritional status, either with parenteral nutrition or oral supplementation, can increase the body weight, skeletal muscle mass, fat mass and quality of life, facilitating the administration of chemotherapy without interruption.8

Malnutrition and weight loss in PC are explained by different mechanisms such as the Warburg effect, loss of appetite, tumour-derived factors which contribute to cachexia, silent subclinical inflammation and pancreatic exocrine insufficiency (PEI).9 PEI seems to be one of the determinant factors of malnutrition in APC due to obstruction of the main pancreatic duct, fibrosis of the gland and loss of pancreatic exocrine tissue. PEI can present with gastrointestinal symptoms such as steatorrhoea as well with signs of malabsorption and deficiency of nutrients and vitamins.10 According to an observational study, the degree of PEI measured by faecal elastase-1 (FE-1) was strongly associated with poor survival in APC.11

Pancreatic enzyme replacement therapy (PERT) is the standard treatment for PEI.12 Patients with APC under PERT gain weight significantly13 and survive longer compared with those who are not receiving PERT in observational studies.14,15 However, the rate of PERT prescription even in the presence of symptoms that could be attributable to malabsorption is low in common practice.16

A previous meta-analysis on PEI in PC reported a preval‎ence of PEI of 44% before surgery, increasing to 74% six months after surgery.17 However, data about the preval‎ence of PEI in APC are limited and heterogeneous and the impact of PERT has not been analysed.

This study aims to assess the preval‎ence and clinical consequences of PEI in patients with APC, alongside the association of PERT with survival and quality of life.

서론

췌장암(PC)은

유럽에서 9번째로 흔한 암이며

악성 종양으로 인한 사망 원인 중 4위를 차지한다.1

췌장암은 1년 생존율이 24%,

5년 생존율이 9%에 불과할 정도로 예후가 매우 불량하다.2

췌장암 생존율은 주로 진단 시 병기에 의해 영향을 받으며,

초기 단계 환자(진단 시 약 10%)의 경우 종양 수술적 절제가 가능하며 5년 생존율은 32%이다.

그러나 약 80%의 환자는

국소 진행성 또는 전이성 질환으로 진단되며,

각각의 5년 생존율은 1%와 3%에 불과하다.3

항암제 치료의 발전에도 불구하고,

진행성 췌장암(APC) 환자의 5년 생존율은 지난 40년간 미미하게만 개선되었습니다.4

이러한 낮은 생존율의 원인은 다중적이며,

생물학적 공격성, 진행된 병기에서의 진단,

그리고 고령 및 동반 질환으로 인해 상당수 환자가 어떠한 치료도 받지 못하는 사실 등이 포함됩니다.5

위암 환자의 낮은 기능 상태는 영양실조 때문이기도 하다.

발병 시점의 환자 중 30%가 영양실조 상태이며,

80%가 체중 감소를 호소하고,

3분의 1 이상이 초기 체중의 10% 이상을 상실했다. 6

식욕부진과 악액질은 APC의 흔한 특징으로,

환자의 항암치료 수용 능력을 저하시키고

생존율 및 삶의 질에 영향을 미친다.7

비경구영양이나 경구 보충제를 통한 영양 상태 개선은

체중, 골격근량, 지방량 및 삶의 질을 향상시켜 항암치료를 중단 없이 시행할 수 있게 한다.8

췌장암에서의 영양실조와 체중 감소는 워버그 효과, 식욕 상실, 악액질을 유발하는 종양 유래 인자, 무증상 잠재성 염증, 췌장 외분비 기능부전(PEI) 등 다양한 기전으로 설명된다.9 PEI는 주췌관 폐쇄, 췌장 섬유화, 췌장 외분비 조직 손실로 인해 APC에서 영양실조의 결정적 요인 중 하나로 보인다. PEI는 지방변과 같은 위장관 증상뿐만 아니라 흡수 장애 및 영양소·비타민 결핍 징후를 동반할 수 있다.10 관찰 연구에 따르면, 분변 엘라스테이스-1(FE-1)로 측정된 PEI 정도는 APC에서 불량한 생존율과 강한 연관성을 보였다.11

췌장 효소 대체 요법(PERT)은

PEI의 표준 치료법이다.12

관찰 연구에서 PERT를 시행 중인 APC 환자는

PERT를 받지 않는 환자에 비해 체중이 유의하게 증가하고13

생존 기간이 연장되었다.14,15

그러나 흡수 장애로 인한 증상이 존재함에도 실제 진료 현장에서는

PERT 처방률이 낮은 실정이다.16

췌장암(PC)

환자의 PEI에 대한 기존 메타분석에서는 수술 전 PEI 유병률이 44%였으나

수술 6개월 후 74%로 증가했다고 보고하였다.17

그러나 APC 환자의 PEI 유병률에 대한 데이터는 제한적이고 이질적이며, PERT의 영향은 분석되지 않았다.

본 연구는 APC 환자에서 PEI의 유병률과 임상적 결과를 평가하고, PERT가 생존율 및 삶의 질과 연관성을 규명하는 것을 목표로 한다.

MethodsData sources and searches

This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria. All studies indexed in Scopus, Embase and Medline reporting the preval‎ence of PEI and/or the effect of PERT in APC outcomes were retrieved up to March 2020. The search strategy is listed in Supplementary Material Methods. Two researchers (DIG and BA) scrutinised all identified studies independently and decided jointly on those for inclusion. When there was a discrepancy, the senior authors (EdM and GC) arbitrated.

Study selection

Inclusion criteria were: (a) prospective observational studies or randomised controlled trials (RCTs) that reported the rate of PEI in patients with APC (locally advanced or metastatic PC); (b) prospective observational studies or RCTs that reported the effect of PERT on outcomes of APC. PEI was defined as an abnormal result on direct and/or indirect pancreatic exocrine function tests.18 Exclusion criteria: (a) PEI due causes other than APC, including pancreatic resection; (b) data presented only on editorials, expert opinion reports, reviews, studies published as abstracts, case reports, letters, studies based on samples lower than 10 patients.

Data extraction and quality assessment

Two authors (DIG and BA) extracted data independently from the included studies using predefined standardised forms; those two authors independently scored the included studies, and two further authors (MK and NP) resolved any disagreement. The quality of observational studies was assessed using the Newcastle-Ottawa scale19 with a total score ≥5 indicative of high quality; the quality of RCTs was assessed using the Jadad system20 with a total score ≥3 indicative of high quality.

Outcomes of interest

The primary outcome was the proportion of patients diagnosed with PEI following the diagnosis of APC. The level of FE-1 of 100–200 µg/g was defined as mild to moderate PEI and <100 µg/g as severe PEI.

Secondary outcomes included symptoms of PEI, coefficient of fat absorption (CFA), body weight, survival, abdominal symptoms, the proportion of prediabetes and/or diabetes mellitus (DM), serum nutritional parameters and quality of life.

APC patients were defined as those diagnosed with unresectable pancreatic cancer (either locally advanced or metastatic disease) following the consensus-based guidelines from the National Comprehensive Cancer Network.21

Data synthesis and statistical analysis

Pooled data were expressed as preval‎ence with 95% confidence interval (CI). Mean and standard deviation (SD) of continuous variables were used for meta-analyses when medians were given. Data for two group comparisons were expressed as relative risk (RR) or risk difference (RD) with 95% CI. Continuous variables were expressed as mean differences (MDs). Stats Direct V3.4 (StatsDirect Ltd, Cheshire, UK) and Review Manager V.5.3 software (Cochrane Collaboration, Oxford, UK) were used to generate forest plots of pooled data using a random effects model to deliver the most conservative estimates. Heterogeneity was eval‎uated using χ2. A value of p<0.1 was considered significant. Statistical heterogeneity was assessed using I2 values with cut-offs of 25%, 50% and 75% to indicate low, moderate and high heterogeneity, respectively.22 Meta-analyses compared PERT versus baseline, PERT versus placebo or PERT versus no treatment.

Subgroup analyses examined high-quality studies, studies with sample sizes ≥30, Western population. Sensitivity analyses considered studies restricted to direct PEI tests, indirect PEI tests and FE-1 tests only. Meta-regression analyses determined the impact of publication year, patient age, gender and type of PEI test on the pooled preval‎ence estimate using Stata SE version 14 software (StataCorp LP, College Station Texas, USA); p<0.05 was considered significant. Publication bias was assessed visually by funnel plots and using p values generated from the pooled preval‎ence of PEI in APC as well as by subgroups according to Begg-Mazumdar and Egger et al.

ResultsCharacteristics of included patients

The PRISMA flow diagram is shown in Figure 1. Eleven studies were included. Study design and characteristics are shown in Table 1. One study was conducted in USA,23 five in Europe,11,13,14,24,25, two in Japan,26,27 one in Australia,28 one in New Zealand29 and one in Korea.30 There were four RCTs,13,27,28,30 three of PERT vs placebo13,28,30 and one of PERT vs no PERT.27 Eight studies had a prospective cohort design11,24–26,29 and one had a retrospective design.14 All seven studies11,14,23–26,29 scored by the Newcastle-Ottawa scale with Selection, Comparability, and Outcome compositions (Supplementary Material Table 1A) were of high quality. The four RCTs13,27,28,30 were all of high quality (Supplementary Material Table 1B). Seven studies reported sufficient data to calculate the pooled preval‎ence of PEI11,23–27,30 and seven the effects of PERT.13,14,26–30

Figure 1.

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Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram. APC: advanced pancreatic cancer; PEI: pancreatic exocrine insufficiency; PERT: pancreatic enzyme replacement therapy; PC: pancreatic cancer.

Table 1.

Characteristic of studies and patients Included.

StudyYearCountryStudy periodDesignPatients enrolled (patients with PC)Age, yearsaMale, n (%)HeadBody-tailMain outcome

Perez et al.23	1983	USA	NR	Prospective	12 (12)	Range 44–81	7 (58)	8	4	Incidence
Bruno et al.13	1998	The Netherlands	1993–1994	RCT	21 (19)	75.8±7, 3	8 (38)	21	0	Effect of PERT
Partelli et al.11	2012	Italy	2007–2009	Prospective	194 (194)	63, (25th and 75th, 55–69)	108 (56)	139	55	Incidence
Sikkens et al.24	2014	The Netherlands	2010–2012	Prospective	32 (24)	71 (60–74)	16 (50)	24	0	Incidence
Woo et al.30	2016	Korea	2011–2014	RCT	67 (67)	63.89±10.14	43 (64)	23	44	Incidence Effect of PERT
Witvliet-Van Nierop et al.25	2017	The Netherlands	2014–2015	Prospective	16 (16)	60.3 (9.5)	8 (50)	10	6	Incidence
Zdenkowski et al.28	2017	Australia	2012–2014	RCT	18 (18)	65.25 (9.5)	9 (50)	8	7	Effect of PERT
Saito et al.26	2017	Japan	2012–2014	Prospective	46 (46)	68 (44–88)	30 (65)	22	23	Incidence Effect of PERT
Saito et al.27	2018	Japan	2014–2016	RCT	88 (88)	68.5 (50–85)	47 (53)	34	54	Incidence Effect of PERT
Dominguez-Munoz et al.14	2018	Spain	2011–2016	Retrospective cohort	160 (160)	70.5 (28–100)	92 (57.5)	93	67	Effect of PERT
Landers et al.29	2019	New Zealand	2013–2015	Prospective	29 (29)	69.4 (8.9)	12 (41.4)	20	6	Effect of PERT

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NR: not reported; PC: pancreatic cancer; PERT: pancreatic enzyme replacement therapy; RCT: randomized clinical trial.

aYear is expressed as mean (standardised deviation), mean (range), median (range) or range.

The patient’s characteristics included in the studies are shown in Table 1. Six hundred and seventy-three APC patients were included, with data on PEI available in 513 patients. The average age of included patients was 66 years and 53% were males. The primary tumour was located at the head of the pancreas in 402 patients (59.7%), at the body-tail in 266 (39.5%), while in the remaining cases the site of the primary lesion was not reported.

Pooled preval‎ence of pancreatic exocrine insufficiency in APC

Data on pancreatic function, PERT composition and administration schedule, and clinical outcomes are presented in Table 2. Four studies reported the rate of patients with previous history of DM.11,13,24,26 PEI was defined by FE-1 <200 μg/g in four studies,11,24,30 by N-benzoyl-L-tyrosyl-P-aminobenzoic acid (NBT-PABA) test in two studies,26,27 by triolein breath test and/or oleic acid breath test and or CFA <93% in one study,23 by CFA<85% and/or FE-1<200 μg/g and/or faecal fat excretion >20 g/d in one study25 and by clinical suspicion and/or weight loss >10% in two studies.14,28 Data about PERT use were reported in all 11 studies: eight studies also reported the length of follow-up11,13,24,26–30 and six presented data about health status.13,25,27–30

Table 2.

Pancreatic function at baseline.

StudyPatients with PC (analysed for PEI)Pre-existing DM (%)PEI diagnostic criteriaPEI (%)Use of PERTType of enzymes (dose)Follow-up (weeks)Health status

Perez et al.23	12 (12)	NR	Triolein breath test Oleic acid breath test CFA<93% CPA<95% 3 Days stool collection after the passage of stool marker	9 (75)	12	Pancreatin (8 tablets per meal)	NR	NR
Bruno et al.13	21 (0)	5 (21)	NR	NR	10	Panzytrat 25,000 (2 capsules per meal, 1 capsule per snack)	4, 8,12	Karnofsky performance status
Partelli et al.11	194 (194)	99 (51)	FE-1<200 μg/g	97 (50)	97	Creon (20,000 Units per meal)	6–12	NR
Sikkens et al.24	24 (24)	10 (42)	FE-1<200 μg/g	16 (67)	4/19	NR	8 (4–16)	NR
Woo et al.30	67 (67)	NR	FE-1<200 μg/g	45 (56)	34 (51)	Norzyme 25,000 (2 capsules per meal 1 capsule per snack)	4, 8,12	PG-SGA, EORTC QLQ-C30
Witvliet-Van Nierop et al.25	16 (15)	NR	CFA<85% FE-1<200 μg/g Faecal fat excretion >20 g/d	8 (53)d	5 (31)	NR	NR	GIQLI
Zdenkowski et al.28	18 (0)	NR	Clinical suspicion of steatorrhea	NR	9	Creon 25,000 (2 capsules per meal 1 capsule per snack)	4-8-20-32-44	EORTC QLQ-C30 PAN 26 PG-SGA
Saito et al.26	46 (36)	23 (50)	NBT-PABA test with urinary PABA recovery	34 (94)	46	Pancrealipase (48,000 UI per meal)	0–16	NR
Saito et al.27	88 (62)	NR	NBT-PABA test with urinary PABA recovery <61%	56 (90)	44	Pancrealipase 12,000 Units (4 capsules per meal)	4-8-16	Gastrointestinal symptoms
Dominguez-Munoz et al.14	160 (74)	NR	Weight loss >10% of body weight and/or Symptoms of PEI	49 (66)	49	Creon 25,000 (2 capsules per meal and 1 capsule per snack)	NR	NR
Landers et al.29	29 (29)	NR	NR	NR	29	Creon 25,000 (2 capsules per meal and 1 capsule per snack)	1–3	EORTC QLQ-C30 QLQ-PAN 26

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AACT: amino acid consumption test; DM: diabetes mellitus; FACIT: Functional Assessment of Chronic Illness Therapy; FACT: Functional Assessment of Cancer Therapy; FE-1: faecal elastase-1; FFE: faecal fat excretion; GIQLI: Gastrointestinal Quality of Life Index; NBT-PABA: N-benzoyl-L-tyrosyl-P-aminobenzoic acid; NR: not reported; PEI: pancreatic exocrine insufficiency; PERT: pancreatic enzyme replacement therapy; PG-SGA: Patient-Generated Subjective Global Assessment; SCT: secretin-cerulein (or pancreozymin) test; SF-36: Short Form 36 Health Survey Questionnaire; EORTC QLQ C30: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; EORTC PAN 26: European Organization for Research and Treatment of Cancer Pancreatic Cancer Module.

A summary of the results of all the performed quantitative syntheses (meta-analyses) is shown in Table 3.

Table 3.

Results of meta-analysis.

VariablePatients, nEffect estimateHeterogeneityPreval‎enceStudies, nTotal patientsNo of PEIPool preval‎ence, % (95% CI)I2(%)p Value

Preval‎ence in advance PC	7	410	265	72 (55–86)	91	<0.0001
Mild vs severe PEI a
Mild PEI	2	261	37	17 (6–31)	84	0.012
Severe PEI	2	261	105	40 (34–46)	0	0.551
Head vs body and/or tail
Head	3	226	105	56 (42–70)	83	<0.0001
Body/tail	2	198	17	32 (1–60)	89	<0.0001
Prediabetic and/or DM vs PEIb
Prediabetes and/or DM	3	264	132	50 (44–56)	0	0.699
PEI	3	254	147	71 (39–95)	94	<0.0001
PERT vs baseline		PERT	Baseline	MD, % (95% CI)
CFA	2	23	23	11.45 (–2.45–25.35)	0	0.11
Body weight	3	54	54	–0.06 (–2.62–2.49)	0	0.96
PERT vs placebo		PERT	Placebo	MD, % (95% CI)
Body weight	3	54	53	3.27 (1.43–5.1)	0	0.0005
Change body weight	2	45	44	1.66 (–0.66–3.98)	60	0.16
PERT vs No PERT		PERT	No PERT	MD, % (95% CI)
Survival	6	269	279	3.78 (1.37–6.19)	58	0.04

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APC: advanced pancreatic cancer; CFA: coefficient of fat absorption; CI: confidence interval; DM: diabetes mellitus; MD: mean difference; PEI: pancreatic exocrine insufficiency; PERT: pancreatic exocrine replacement therapy.

aIncluded studies that simultaneously reported preval‎ence of mild and severe PEI.

bIncluded studies that simultaneously reported preval‎ence of PEI and prediabetic and/or DM.

As for the pooled preval‎ence of PEI, 410 patients from seven studies were included. The pooled preval‎ence of PEI was 72% (95% CI: 55–86%) with high statistical heterogeneity (I2 = 91%) (Figure 2(a)). Two studies reported preval‎ence of PEI depending on tumour location.11,23 The pooled preval‎ence of PEI in tumours in the pancreatic head was 56% (95% CI: 42–70%, I2 = 83%) and in the body-tail 32% (95% CI: 1–60%, I2 = 89%) with significantly higher preval‎ence in tumours located in the head of the pancreas (RR = 3.36, 1.07-10.54; p = 0.04). (Figure 2(b)).

Figure 2.

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a) Pooled preval‎ence of pancreatic exocrine insufficiency (PEI). b) Relative risk of PEI between tumors located in the head of the pancreas and body-tail.

The pooled preval‎ence of pre-diabetes and/or DM was 50% (95% CI: 44–56%, I2 = 0%). In the studies reporting the preval‎ence of PEI and pre-diabetes and/or DM, the pooled preval‎ence of PEI was 71% (95% CI: 39–95%, I2 = 94%), without any statistically significant difference between PEI and pre-diabetes and/or DM (RR: 1.41, 0.86–2.30; p = 0.173, three studies)11,24,26 (see Supplementary Material Figures 2A and 2B).

Only two studies reported the severity of PEI based on FE-1.11,30 The pooled preval‎ence of mild to moderately severe PEI was 17% (95% CI: 6–31%, I2 = 84%) and that of severe PEI 40% (95% CI: 34–46%, I2 = 0%) (see Supplementary Material Figure 3).

Figure 3.

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Clinical outcomes of patients under pancreatic enzyme replacement therapy (PERT) versus placebo. CI: confidence interval.

Subgroup analyses found that study quality, RCT design and sample size did not affect the preval‎ence of PEI in APC or cause statistical heterogeneity. Studies performed in Western countries reported a lower preval‎ence of PEI compared with the primary analysis 57% (95 CI: 46–67%) with lower heterogeneity (I2 = 35%) (see Supplementary Material Table 2). Sensitivity analyses showed that studies that used FE-1 had a lower pooled preval‎ence of PEI 60% (95% CI: 46–72%) and lower heterogeneity (I2 from 91% to 72%). The sensitivity analyses found that primary meta-analysis results were also affected by the use of indirect tests to diagnose PEI (81%, 95% CI: 64–94%; I2 = 76%) (Supplementary Material Table 3).

Meta-regression identified the type of test for the diagnosis of PEI (p = 0.044) as a contributing factor for heterogeneity. The model which included variables statistically associated with heterogeneity in the univariate analyses explained 85% of heterogeneity among studies. (Supplementary Material Table 4).

There were insufficient data for quantitative meta-analysis of the effects of PERT in quality of life, gastrointestinal symptoms and serum nutritional parameters.

Effect of PERT in patients with APC

The clinical outcomes of PERT versus baseline are presented in Table 3 and Supplementary Material Figure 1. Two studies13,23 reported the results in terms of changes of CFA with pooled results showing an increase of CFA after PERT versus baseline, albeit without statistical significance (80.45±20.8 vs 68.9±27.4; MD: 11.45, –2.45–25.35; p = 0.11) with no heterogeneity (I2 = 0%). Pooled data from three studies13,28,30 did not find any change in body weight after 8 weeks of PERT in comparison to baseline (p = 0.96). The clinical outcomes of patients under PERT versus placebo are displayed in Figure 3 and summarised in Table 3. Pooled data from three studies13,28,30 found that PERT led to a significant increase in body weight when compared to placebo after 8 weeks of treatment (MD: 3.27; 1.43–5.1; p = 0.0005). Pooled data from two studies13,30 reporting the change in body weight after PERT as compared to placebo did not show a statistically significant difference (p = 0.16).

The effect of PERT on survival is summarised in Table 3 and presented in Figure 4. Pooled data of six studies,11,14,26–28,30 demonstrated that the survival of patients who received PERT was significantly longer compared to that of those who did not (12.6±12.9 months vs 8.7±10.7 months; MD: 3.78, 1.37–6.19; p = 0.002).

Figure 4.

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Effect of pancreatic enzyme replacement therapy (PERT) on survival. CI: confidence interval.

Publication bias

Funnel plots for publication bias are presented in Supplementary Material Figure 4. There was no evidence of publication bias either for the analysis on the preval‎ence of PEI in APC or for that on the effect of PERT on survival, body weight or CFA (Begg-Mazumdar and Egger tests p>0.1).

Discussion

This systematic review and meta-analysis conducted in patients with APC found that 72% of patients have PEI. PEI was not restricted to patients with the tumour in the head of the pancreas, as almost one-third (32%) of patients who had the tumour located in the body-tail were also found to have PEI. Treatment of PEI was associated with significantly longer survival compared with no treatment (12.6 vs 8.7 months, p = 0.002), and with the improvement of body weight and abdominal symptoms. Collectively, these results suggest that PEI should be carefully investigated in APC patients, as malnutrition, cachexia and weight loss have a negative impact on survival and quality of life. Indeed, the survival of patients with APC can be affected, among several other factors, by their nutritional status. Malnutrition, weight loss, sarcopenia and cachexia are related to chemotherapy-induced toxicity and worsening of quality of life and survival in several reports.7,8 Malnutrition in APC is multifactorial, but PEI leading to maldigestion and secondary malnutrition plays a major role.9,31 Patients with PEI reported the worst quality of life mainly due to difficulties managing gastrointestinal complaints, diet and digestion.32

In the present study, PEI was diagnosed in over three out of four patients with APC, and there was a threefold increase in the preval‎ence of PEI in tumours located in the head of the pancreas compared to those located in the body-tail; 40% of those patients had severe PEI based on FE-1 levels.

Sensitivity and subgroup analysis showed that the preval‎ence of PEI decreased when FE-1 was used as well as when the studies were performed in Western countries. While FE-1 testing is easy to perform and has a rather high sensitivity, the specificity of the test in patients with APC is very low (22%),33 and this result is therefore not unexpected. The accuracy of FE-1 is higher in other pancreatic disorders, such as chronic pancreatitis, and its use in APC needs further investigation.

PERT is the standard treatment for PEI in patients with all pancreatic diseases. Benefits of PERT in APC were reported in several studies. A population-based study from the UK15 showed that PERT in patients with pancreatic adenocarcinoma was associated with increased survival; however, only 21% of those patients were under PERT, suggesting that awareness of the importance of such treatment is limited among physicians taking care of PC patients. In a retrospective study from Spain,14 PERT in PC patients with PEI was associated with longer survival compared to no treatment. The present meta-analysis shows that PERT is significantly associated with longer survival in patients with APC with a difference of about four months. Notably, such differences are unusual in studies on the treatment of APC.34 However, no data were available regarding disease stage, active treatments and performance status of patients and, therefore, residual confounding cannot be excluded and the effect of PERT on survival should be considered with caution.

While PERT has been shown to increase body weight, quality of life and survival in patients with PC,13,14,29 its use is not widespread. Forsmark et al.35 noticed that only 21.9% of PC patients received PERT and that prescription was adequate in only 5.5%. Similar findings were reported in a study on APC patients from Australia in which only 21% of patients with malabsorption were prescribed PERT.16 The reasons for under-treatment may be explained by lack of awareness of healthcare professionals and/or low level of evidence for a clinically relevant improvement in outcomes. Two recent randomised trials, both conducted on small cohorts, demonstrate negative results. Woo et al.,30 randomised 67 APC patients to PERT or placebo. PERT did not reduce weight loss, and it did not improve quality of life nor survival. A Japanese study27 randomised 88 APC patients to PERT or no treatment. After eight weeks, there was no significant difference in change of BMI or in levels of serum nutritional markers. However, in both studies, the random protocol was applied regardless of PEI status and the doses of PERT per day were low based on guideline recommendations (150,000 Ph. Eur units of Norzyme – range from 25,000–257,500 Ph. Eur units per day - in the study of Woo et al. and 144,000 lipase units per day in the study of Saito et al.27) A subgroup analysis among patients with tumours located in the head of the pancreas, who have a higher rate of PEI, demonstrated that there was an improvement in symptoms and nutrition in patients under PERT.30

The main limitations of this systematic review and meta-analysis are the heterogeneity and small size of the included studies and the fact that most of them are prone to bias, as only four of them were RCTs. Another limitation is that only two studies employed the CFA, which is currently the reference method to eval‎uate pancreatic function,10 allowing investigation on the effect of PERT on pancreatic function. Heterogeneity among studies also prevented the quantitative assessment of the effect of PERT on quality of life, gastrointestinal symptoms and serum nutritional markers due to different time-points and scales; therefore, no definitive conclusions can be made on those outcomes.

Large multicentre RCTs with proper sample size calculation are needed to eval‎uate the effect of PERT in APC with diagnosed PEI. However, until new data are published, based on the results of the present meta-analysis, PERT should be considered as an essential part of the multidisciplinary treatment of patients with APC.

In conclusion, this study shows that PEI is present in approximately 75% of patients with APC and that its treatment with PERT can prolong survival. PERT should be considered as a part of the best standard of care in patients with APC.

Supplemental Material

sj-pdf-1-ueg-10.1177_2050640620938987 - Supplemental material for Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: A systematic review and meta-analysis

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Supplemental material, sj-pdf-1-ueg-10.1177_2050640620938987 for Pancreatic exocrine insufficiency and pancreatic enzyme replacement therapy in patients with advanced pancreatic cancer: A systematic review and meta-analysis by Daniel de la Iglesia, Bartu Avci, Mariia Kiriukova, Nikola Panic, Maryana Bozhychko, Vasile Sandru, Enrique de-Madaria and Gabriele Capurso in United European Gastroenterology Journal

Acknowledgments

This study was conducted through Pancreas 2000, which is a European educational and scientific pancreatology research programme initiated by the Karolinska Institutet in Stockholm, Sweden, and the European Pancreatic Club and is supported by United European Gastroenterology.

Footnotes

Declaration of conflicting interests: The authors have no conflicts of interest to declare.

Funding: The authors received no financial support for the research, authorship and/or publication of this article.

Ethics approval: Not required

Informed consent: Not required

ORCID iDs

Bartu Avci https://orcid.org/0000-0003-2156-238X

Enrique de-Madaria https://orcid.org/0000-0002-2412-9541

Gabriele Capurso https://orcid.org/0000-0002-0019-8753

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