Effect of prehabilitation in patients undergoing hepatobiliary and pancreatic cancer resections: A systematic review and meta-analysis

Abstract

BACKGROUND

Hepatobiliary and pancreatic cancers are often associated with high morbidity and mortality. Surgical intervention remains the cornerstone for curative treatment. However, Due to the complexity of these procedures, patients often experience postoperative complications. Prehabilitation has been suggested as a tool to decrease postoperative morbidity and improve recovery by optimising patients preoperatively to handle the stress of surgery.

AIM

To evaluate the effectiveness of prehabilitation in patients undergoing hepatobiliary and pancreatic cancer resections.

METHODS

Standard medical databases such as MEDLINE, EMBASE, PubMed, and Cochrane Library were searched to find randomised, controlled trials comparing prehabilitation vs no-prehabilitation before hepatic, biliary, or pancreatic cancer resections. All data were analysed using Review Manager Software 5.4, and the meta-analysis was performed with a random-effect model analysis.

RESULTS

A total of 8 studies were included (n = 568), recruiting adult patients undergoing hepatic, biliary, or pancreatic cancer resections. In the random effect model analysis, prehabilitation was associated with fewer postoperative complications compared to no prehabilitation [risk ratio (RR): 0.79, 95%CI: 0.66-0.95, Z = 2.52, P = 0.01]. No statistically significant difference was found in postoperative readmission rate (RR: 1.31, 95%CI: 0.79-2.17, Z = 1.05, P = 0.29), major complications (RR: 1.08; 95%CI: 0.61-1.92, Z = 0.28, P = 0.78), length of stay (standardised mean difference: -0.11, 95%CI: -0.31 to 0.1, Z = 1.05, P = 0.29), or mortality (RR: 0.28, 95%CI: 0.01-6.51, Z = 0.79, P = 0.43).

CONCLUSION

Prehabilitation was found to be effective in reducing postoperative complications following surgical intervention for hepatobiliary or pancreatic cancer.

Key Words: Prehabilitation; Hepatobiliary cancer; Pancreatic cancer; Cancer resection; Postoperative complications

Core Tip: Hepatobiliary and pancreatic cancer surgeries are complex procedures that carry a high risk of postoperative morbidity. This meta-analysis of 8 randomised controlled trials found that prehabilitation–focused on preparing patients physically, nutritionally, and mentally before surgery–significantly reduces the overall rate of complications. While no clear differences were seen in readmission, mortality, or length of stay, the data suggest a valuable role for prehabilitation in improving recovery following major abdominal cancer operations. These results highlight its potential for integration into standard preoperative care.

INTRODUCTION

Hepatobiliary and pancreatic cancers are among the most lethal malignancies worldwide. In 2020, liver and pancreas cancers alone accounted for 1623000 new cases and 1241000 deaths worldwide[1]. Surgical intervention is a cornerstone in the management of these cancers, often integrated into a multifaceted treatment approach that may include systemic therapies, radiation, and neoadjuvant strategies[2]. However, operations involving the liver, pancreas, and gallbladder are highly invasive procedures, with high mortality and morbidity rates[3]. These complex surgeries are associated with various postoperative complications, including, but not limited to, pancreatic fistulas, gastroparesis, intra-abdominal abscesses, and bile leakage[4,5]. Previous studies have demonstrated that pancreatic cancer patients who undergo surgical resection have a median survival of 27.1 months and a five-year survival rate of 34.5%[6]. Given the poor prognosis and high complication rate, patient care strategies that aim to improve postoperative recovery and outcomes must be developed.

Prehabilitation can be defined as a multifaceted strategy for optimizing patients preoperatively to withstand surgical stress[7]. It includes interventions targeting various aspects of a patient's overall health, such as nutrition, exercise capacity, and psychological well-being[7]. Currently, such interventions are more widely used postoperatively, with the example of the enhanced recovery after surgery program, which has been proven to shorten hospital stays after surgery[8]. Several studies have revealed a correlation between poor preoperative cardiopulmonary reserve and increased postoperative complications[7]. Prehabilitation has been shown to improve patient functional capacity leading up to surgery and reduce the incidence of severe postoperative complications[9]. Furthermore, patients tend to be more accepting of lifestyle interventions in the preoperative period, possibly improving adherence[10]. A previous meta-analysis has found that prehabilitation was linked with a trend towards fewer complications and shorter hospital stays, however, they were limited to their study selection, which included multiple non-randomised controlled trials (RCTs) and cohort studies[11]. This meta-analysis is the first to provide a comprehensive review of all RCTs available, comparing prehabilitation to no prehabilitation in patients undergoing surgery for hepatobiliary and pancreatic cancer.

MATERIALS AND METHODS

This meta-analysis was conducted in accordance with the preferred reporting items for a systematic review and meta-analysis, through the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines[12].

Data sources and search strategy

For this systematic review and meta-analysis, an electronic database search of MEDLINE, EMBASE, PubMed, and The Cochrane Library was conducted for RCTs. Articles published until January 2025 were searched for, using the Medical Subject Headings “prehabilitation liver cancer”, “prehabilitation pancreatic cancer”, and “prehabilitation hepatobiliary cancer”. Boolean operators (AND, OR, NOT) were used to refine the search results. The titles from the search results were independently reviewed by two authors and were determined to either be included or excluded from the study. The referenced list of the included studies was searched to find any additional articles. The accuracy of the extracted data was later confirmed by a third author.

Study selection

Only RCTs involving human participants directly comparing the effects of prehabilitation to no prehabilitation in hepatobiliary or pancreatic cancer patients awaiting surgery were chosen. We excluded quasi-experimental studies, cohort studies, and case-control studies. There was no restriction on the country of origin for the studies, language, or hospital of origin. The main outcomes we were searching for were postoperative complications, length of stay (LOS), readmissions, and mortality. The process and results of the literature retrieved are shown in Figure 1.

Figure 1  Preferred Reporting Items for Systematic Reviews and Meta-analyses flow chart explaining identification of studies via databases.

Data extraction

Data from included studies was extracted by two independent reviewers into a predefined meta-analysis form. A third reviewer confirmed the accuracy of the data. There were no discrepancies in trial selection or data extraction between the reviewers.

Statistical analysis

The software package Review Manager 5.4[13] by the Cochrane Collaboration was utilised for the statistical analysis. The risk ratio (RR) with a 95%CI was calculated for binary data, and the standardised mean difference (SMD) with a 95%CI was used for continuous data variables. The random effects model[14,15] was used to calculate the combined outcomes for dichotomous variables. Heterogeneity was explored through the χ² test, with significance set at P < 0.05, and was quantified[16] using I², with a maximum value of 30% signifying low heterogeneity. If the standard deviation was not available, it was calculated through the guidelines set out by the Cochrane Collaboration[17]. The Mantel-Haenszel method was used to calculate odds ratio under the random-effect model analysis[18]. Only RCTs that were clinically homogenous and had tested the same variables, such as 6-minute walking distance or LOS, were pooled together.

In a sensitivity analysis, 0.5 was added to each cell frequency for trials in which no event occurred in either the treatment or control group, according to the method recommended by Deeks et al[19]. This process assumed that both groups had the same variance, which may not have been confirmed, and variance was either estimated from the range or the P value. The estimate of the difference between both techniques was pooled, depending on the effect weights in the results determined by each trial’s estimated variance. Forest plots were used for graphical display. The square around the estimate stood for the accuracy of the estimation (sample size), and the horizontal line represented the 95%CI. The methodological quality of the included trials was initially assessed by the Cochrane trial quality assessment tool[17].

RESULTS

The primary database search led to thirty studies, of which twenty-two were excluded after initial screening. The final review included eight studies (Figure 1).

Characteristics and demographics of included studies

Eight RCTs on 568 patients were included in our updated comprehensive systematic review comparing patient outcomes between prehabilitation and no prehabilitation in patients undergoing surgical intervention in the form of resection for hepatobiliary or pancreatic cancer. Principles advised by the Cochrane Collaboration were used in this analysis. The trials included were studied in Spain, the United Kingdom, Canada, Denmark, Japan, and United States. Primary demographic characteristics of the studies included are specified in Table 1, and the protocol used in each study is given in Table 2[20-27].

Table 1 Characteristics of included studies.

Ref.	Country	Operation	Number of recruited patients	Age in years	Female:male	Duration of follow up	Trial running time
Ausania et al[20], 2019	Spain	Pancreaticoduodenectomy
Prehabilitation			18	66.1 ± 10.51	9:9
No prehabilitation			22	65.7 ± 10.751	9:13	18 days	2015-2017
Dunne et al[21], 2016	United Kingdom	Liver resection
Prehabilitation			20	61 ± 2.51	7:13	4 weeks	2011-2013
No prehabilitation			17	62 ± 4.751	4:13
Gade et al[22], 2016	Denmark	Pancreatic cancer resection
Prehabilitation			19	68 ± 7.751	7:12	30 days	2012-2012
No prehabilitation			16	69 ± 6.51	10:6
Griffiths et al[23], 2024	Canada	Open and laparoscopic hepatic, pancreatic, and colorectal resection
Prehabilitation			33	65 ± 3.251	12:21	12 weeks	Not reported
No prehabilitation			30	63 ± 2.51	13:17
Kaibori et al[24], 2013	Japan	Hepatectomy
Prehabilitation			25	68 ± 9.1	8:17	6 months	2008-2010
No prehabilitation			26	71.3 ± 8.8	7:19
McIsaac et al[25], 2022	Canada	Open and minimally invasive hepatobiliary, colorectal, thoracic, urologic cancer resections
Prehabilitation			94	74 ± 7	57:34	30 days	2017-2019
No prehabilitation			88	74 ± 6	46:42
Mikkelsen et al[26], 2022	Denmark	Pancreatic, biliary tract, non-small cell lung cancer resections
Prehabilitation			41	72.1 ± 1.81	22:19	13 weeks	2018-2020
No prehabilitation			43	71.5 ± 1.71	26:17
Ngo-Huang et al[27], 2024	United States	Pancreatic cancer resection
Prehabilitation			75	66.1 ± 8.5	26:49	3 months	2017-2021
No prehabilitation			76	66.2 ± 8.2	33:43

¹Standard deviation calculated from range.

Table 2 Treatment protocol adopted in included studies.

Ref.	Prehabilitation	No prehabilitation
Ausania et al[20], 2019	5 days training in outpatient clinic and daily training at home. Nutritional support. Endocrine and exocrine pancreatic management	Dietary advice, physical activity recommendations
Dunne et al[21], 2016	12 personalized exercise sessions over 4 weeks period	Standard care
Gade et al[22], 2016	Oral supplement 7 days before surgery	No intervention
Griffiths et al[23], 2024	Supplement solutions. 20 g protein isolate powder day 30-6 pre-operation. Immunonutrition 3 times a day 5-1. Carbohydrate rich solution night and morning of surgery	Placebo supplements, standard care
Kaibori et al[24], 2013	Patient tailored exercise program. Dietary advice	Dietary advice
McIsaac et al[25], 2022	Strength training. Aerobic exercise. Flexibility training	Received physical activity recommendations pamphlet
Mikkelsen et al[26], 2022	Exercise (60 minutes sessions twice a week). Protein supplement after each session. Individualized walking program. 2 nurse led counseling sessions	No interventions
Ngo-Huang et al[27], 2024	Aerobic and resistance training. Nutrition counseling	Recommended to stay active and given informational material

Methodological quality of included studies

The methodological quality of the included RCTs is shown in Table 3[20-27]. Randomisation was achieved through either block randomisation, computer generation, the Pocock-Simon minimisation method, envelopes, or was not reported. Concealment was reported in two studies.

Table 3 Quality assessment of included studies.

Ref.	Randomization technique	Power calculation	Blinding	Intention-to-treat	concealment	Inclusion criteria	Exclusion criteria
Ausania et al[20], 2019	Not reported	Yes	Single blind	Not reported	Not reported	Yes	Yes
Dunne et al[21], 2016	Random number block	Not reported	Single blind	Not reported	Not reported	Yes	Yes
Gade et al[22], 2016	Envelopes	Yes	Single blind	Yes	Yes	Yes	Yes
Griffiths et al[23], 2024	Computer generated	Not reported	Double blind	Not reported	Not reported	Yes	Yes
Kaibori et al[24], 2013	Not reported	Not reported	Not reported	Not reported	Not reported	Yes	Yes
McIsaac et al[25], 2022	Computer generated	Yes	Double blind	Yes	Yes	Yes	Yes
Mikkelsen et al[26], 2022	REDCap application	Yes	Single blind	Not reported	Not reported	Yes	Yes
Ngo-Huang et al[27], 2024	Pocock-Simon minimization method	Yes	No blinding	Not reported	Not reported	Yes	Yes

Outcome of primary and secondary variables

Total postoperative complications: A total of 5 studies on 337 patients undergoing open and laparoscopic surgery for hepatobiliary or pancreatic cancer reported total postoperative complications. The pooled analysis found that patients who underwent prehabilitation had significantly fewer postoperative complications (RR: 0.79, 95%CI: 0.66-0.95, Z = 2.52, P = 0.01). No statistically significant heterogeneity was observed among trials [Tau² = 0.00, χ² = 0.91, df = 4 (P = 0.92), I² = 0%; Figure 2A][20-22,24,25].

Figure 2 Forest plot. A: Forest plot showing total postoperative complications represented in risk ratio with 95%CI; B: Forest plot showing severe postoperative complications represented in risk ratio with 95%CI; C: Forest plot showing length of hospital stay represented in standardised mean difference with 95%CI; D: Forest plot showing postoperative readmission represented in risk ratio with 95%CI; E: Forest plot showing mortality represented in risk ratio with 95%CI.

Severe postoperative complications (CD ≥ 3)

A total of 4 studies on 216 patients undergoing open and laparoscopic surgery for hepatobiliary or pancreatic cancer reported the incidence of severe postoperative complications. The pooled analysis found no statistically significant difference between both groups (RR: 1.08, 95%CI: 0.61-1.92, Z = 0.28, P = 0.78). No statistically significant heterogeneity was observed among trials [Tau² = 0.00, χ² = 0.70, df = 3 (P = 0.87), I² = 0%; Figure 2B][20,21,23,27].

Length of hospital stay

A total of 7 studies on 505 patients undergoing open and laparoscopic surgery for hepatobiliary or pancreatic cancer reported the length of hospital stay. The pooled analysis found no statistically significant difference between both groups (SMD: -0.11, 95%CI: -0.31 to 0.1, Z = 1.05, P = 0.29). No statistically significant heterogeneity was observed among trials [Tau² = 0.02, χ² = 7.51, df = 6 (P = 0.28), I² = 20%; Figure 2C][20-22,25-27].

Postoperative readmissions

A total of 5 studies on 370 patients undergoing open and laparoscopic surgery for hepatobiliary or pancreatic cancer reported postoperative readmission. The pooled analysis found no statistically significant difference between both groups (RR: 1.31, 95%CI: 0.79-2.17, Z = 1.05, P = 0.29). No statistically significant heterogeneity was observed among trials [Tau² = 0.00, χ² = 2.62, df = 4 (P = 0.62), I² = 0%); Figure 2D][20-22,25,27].

Mortality

A total of 3 studies on 126 patients undergoing open and laparoscopic surgery for hepatobiliary or pancreatic cancer reported mortality. The pooled analysis found no statistically significant difference between both groups (RR: 0.28, 95%CI: 0.01-6.51, Z = 0.79, P = 0.43; Figure 2E)[20,22,24]. Heterogeneity was not assessed due to the lack of mortality in trials, results should be interpreted with caution.

DISCUSSION

Eight RCTs with a combined total of 568 patients (291 who underwent prehabilitation and 277 who did not) were included in our systematic review and meta-analysis comparing outcomes of patients who received prehabilitation vs those who did not prior to surgical resection of hepatobiliary or pancreatic cancer. Our results suggest that prehabilitation could serve as an effective tool to decrease overall postoperative morbidity. Our findings revealed no significant difference between groups in the incidence of severe complications, LOS, readmission rates, and mortality. However, the paucity of RCTs and limited available high-quality evidence on the subject may undermine the validity and generalisability of the findings, potentially obscuring true effects that may exist across real-world populations.

Two similar previously published meta-analyses were identified: (1) Deprato et al[28] in 2022 titled “Surgical outcomes and quality of life following exercise-based prehabilitation for hepato-pancreatico-biliary surgery: A systematic review and meta-analysis”; and (2) Lambert et al[29] in 2021 titled “The impact of prehabilitation on patient outcomes in hepatobiliary, colorectal, and upper gastrointestinal cancer surgery: A PRISMA-accordant meta-analysis”. These studies have discussed similar outcomes to the ones we reported, however, the reliability of their results is compromised by their study selection, including several non-RCTs. Our study was the first of its kind to include strictly all available RCTs on the matter, providing more thorough, high-quality evidence and improved insight into the effects of prehabilitation. It is important to note that both studies found significant reductions in postoperative LOS in prehabilitation groups. While our findings did reveal a trend towards shorter hospital stays, no statistically significant difference was observed. Moreover, both studies found no significant reduction in postoperative complications, whereas our analysis did. Such discrepancies may be attributed to variations in the prehabilitation protocols used across the studies, as well as differences in surgical complexity, patient populations, or postoperative care practices. Additionally, the relatively small sample size in some of the included studies may have limited the ability to detect a significant effect.

A review of the existing literature shows that this meta-analysis and systematic review is the most comprehensive and up-to-date review on the effect of prehabilitation on patients undergoing hepatobiliary or pancreatic cancer resections. However, several limitations exist that may undermine our findings. Firstly, due to our strict inclusion criteria of only RCTs, our analysed population sample was relatively small, which impedes our ability to draw generalised conclusions about real-world populations. Secondly, employed interventions significantly differed as prehabilitation was either multimodal, nutritional, or exercise-based. Furthermore, postoperative rehabilitative care also varied between included trials, introducing further heterogeneity across patient populations. Thirdly, studies included in our analysis had relatively short follow-up durations, meaning the long-term effects of prehabilitation are yet to be adequately explored. Fourthly, several included RCTs also enrolled patients undergoing surgical resection for other gastrointestinal cancers (e.g., colorectal), potentially skewing results and not reflecting real-world populations. Finally, as shown in Figure 2A[20,21,23-25], several methodological aspects, such as blinding and randomisation techniques, have not been reported, possibly introducing bias into respective trials. Further research should aim to address such gaps across the literature to provide valuable insight into the long-term effects of prehabilitation.

CONCLUSION

Prehabilitation may be a beneficial strategy to reduce postoperative complications and improve outcomes in patients undergoing surgery for hepatobiliary or pancreatic cancer. Despite these results, further research is required to draw generalised, long-term conclusions.