Background

The concept of enhanced recovery after surgery (ERAS) regimen was first introduced by Kehlet in 1997 [1]; it was then gradually accepted and widely used in nearly all types of surgeries. Clinical evidence has proved that ERAS not only improves clinical outcomes and quality of care, but also significantly reduces the cost of hospitalization [2,3,4,5,6]. However, the majority of the clinical evidence regarding the benefits of ERAS describes short-term outcomes; the long-term benefits of ERAS are not fully elucidated, especially with respect to cancer surgeries.

Due to the increasing number of cancer cases, the proportion of cancer surgeries among all surgeries is increasing worldwide. Patients undergoing cancer surgeries commonly need neoadjuvant chemotherapy afterwards, and the on-time initiation and completion of chemotherapy after surgery are critical for the prognosis [7], as recurrence and metastasis can directly influence quality of life and long-term survival. The short-term benefits of ERAS are postulated to be associated with its long-term benefits [8], but this has not been fully verified for cancer surgeries. Thus, we conducted a literature search to identify studies on oncologic and long-term outcomes that examined: (1) ERAS versus conventional care, (2) high adherence to ERAS versus low adherence, and (3) the effects of altering one single item within the ERAS protocol.

Methods

We construct the framework of this systematic review in accordance with the 2009 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [9]. The PRISMA checklist is presented in Additional file 1. The protocol of this systematic review was registered in INPLASY with the registration number INPLASY202150099, and the link https://inplasy.com/inplasy-2021-5-0099/.

Literature search

The Pubmed, Cochrane Library, Embase, and Web of Science databases were searched from Jan 2000 to April 2021. The key terms were “ERAS” or “enhanced recovery” or “fast track”, “oncologic outcome”, “recurrence”, “metastasis”, “long-term outcomes”, “survival”, “cancer surgery”, and various combinations of these key terms were used. The detailed search strategy in Pubmed was shown as followed:

#1 “Enhanced Recovery After Surgery”[Mesh]

#2 ((Enhanced Recovery After Surgery) OR (ERAS)) OR (fast track)

#3 Cancer Surgery

#4 (#1 OR #2) AND #3

#5 ((((((oncologic outcome) OR (recurrence)) OR (metastasis)) OR (long-term outcomes)) OR (survival)) OR (cancer specific death)) OR (oncologic)

#6 #4 AND #5

The detailed search strategies in other databases were presented in Additional file 2. The reference lists of the included studies were checked for potentially eligible articles. The languages of the full-text articles were restricted to English and Chinese.

Inclusion and exclusion criteria

The inclusion criteria included studies comparing ERAS and conventional care, comparing different levels of adherence to ERAS, examining alterations of one single item within the ERAS protocol, studies with adult patients (> 18 years old) undergoing cancer surgery, studies describing oncologic outcomes (return to intended oncologic treatment after surgery (RIOT), recurrence, metastasis, and cancer-specific survival) or long-term outcomes (overall survival and quality of life), and prospective or retrospective studies. Exclusion criteria included studies of pediatric surgery, studies describing only short-term outcomes, studies without full text, review articles, or case reports.

Data extraction

Two reviewers (QP and LD) independently extracted data from all included articles, which included the author, publication time, study design, patient age, major diagnosis, surgical type, patient groups and sample size, key elements of the ERAS protocol, oncologic and long-term outcomes, and findings. Disagreements were resolved through consensus between reviewers; if necessary, an additional reviewer was consulted to resolve the dispute.

Data analysis

The methodological quality was evaluated by the Newcastle-Ottawa Scale (NOS) for cohort studies and by the Jadad score for RCTs. The highest NOS score was of 9 stars and the highest Jadad score was 7. Information on major outcomes of interest was recorded, including oncologic outcomes (RIOT, recurrence, metastasis, and cancer-specific survival), long-term overall survival, and quality of life.

Results

Literature search and retrieval

A total of 845 relevant publications were identified through the keywords. The full versions of 35 articles were retrieved after screening and conducting a detailed selection process, and 26 articles [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35] eventually met the inclusion criteria and underwent data extraction. The details of the screening process are presented in Fig. 1.

Fig. 1
figure 1

PRISMA flowchart of systematic strategy

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Study characteristics

The characteristics and quality of the included articles are presented in Table 1. Of these 26 articles, 3 were randomized trials [12, 13, 15], which were evaluated by Jadad score, and the other 23 were prospective or retrospective cohort studies, which were evaluated by the NOS. Eighteen articles compared conventional care with ERAS [10,11,12,13,14,15,16,17,18,19,20,21, 29,30,31,32,33,34], 7 studies compared high adherence to ERAS with low adherence [16, 22,23,24,25,26, 34], and 4 studies [27,28,29, 35] investigated the outcome of one single item altered within ERAS protocol. The elements of the ERAS protocol in each article are presented in Table 2. The number of ERAS elements in the included articles ranged from 3 to 18, and 17 articles described a protocol containing more than 10 elements [11, 13,14,15,16,17,18, 21, 22, 24, 26, 27, 29, 30, 32,33,34].

Table 1 Characteristics of included studies
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Table 2 ERAS protocol elements in the included studies
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Outcomes and findings

The outcomes and findings of the included studies are displayed in Table 3. Seventeen studies described oncologic outcomes [11, 12, 16,17,18,19,20,21,22,23, 25, 28,29,30,31, 33, 35], and 20 studies described long-term outcomes [10,11,12,13,14,15,16, 22,23,24,25,26,27,28,29,30,31,32,33,34].

Table 3 Effects of ERAS on oncologic and long-term outcomes
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Non-ERAS vs ERAS

Twelve studies [10,11,12,13,14, 16, 29,30,31,32,33,34] reported long-term overall survival (OS), and the follow-up time ranged from 10 months to 10 years. Four studies [14, 31, 33, 34] showed ERAS was associated with increasing long-term OS, while the others found no differences between conventional care and ERAS. One study [15] reported quality of life, and the results showed that ERAS improved 6-month quality of life after surgery.

Three studies reported long-term cancer-specific survival (CSS) [11, 12, 33], and 4 studies reported long-term disease-free survival (DFS) [16, 29,30,31].The follow-up time ranged from 10 months to 10 years, 1 study showed that ERAS could improve CSS [33] and DFS [30], while the others found no differences. One study [31] reported recurrence and metastasis, the result found no difference between conventional care and ERAS.

Five studies [17,18,19,20,21] reported the outcomes of RIOT; 2 out of the 5 studies showed a reduced interval from surgery to RIOT with the ERAS group [18, 21], 1 showed improvement in RIOT completion with ERAS [20], 1 showed an improvement in the rate of on time to RIOT with ERAS [19], and 1 showed no differences in the completion of RIOT and the interval from surgery to RIOT between non-ERAS and ERAS groups [17].

High adherence to ERAS vs low adherence to ERAS

Seven studies compared high adherence to ERAS and low adherence to ERAS [16, 22,23,24,25,26, 34]. Long-term OS was reported in six studies, and the follow-up time ranged from 2 to 5 years. Half of the studies showed no differences in OS between high and low adherence [16, 22, 26], and half showed improvements in OS by high adherence to ERAS [23, 24, 34]. Two studies reported DFS [16, 25]; one showed that high adherence to ERAS could improve 3-year DFS [25], and the other did not find any difference [16]. One study showed that high adherence to ERAS could improve 5-year CSS [23], 2 studies reported that high adherence to ERAS had no effect on 3-year metastasis or 5-year recurrence [22, 23], and 1 study showed that high adherence to ERAS reduced the interval from surgery to RIOT [25].

Alteration of one single item within ERAS protocol

Four studies reported the effect of altering one single item within the ERAS protocol on long-term survival and local recurrence [27,28,29, 35]. The follow-up time ranged from 10 months to 5 years. Two studies compared laparoscopic with open surgery within the ERAS protocol, of which, 1 study revealed improvements in OS with laparoscopic surgery [27], and the other did not find any difference [29]. One study compared restrictive with liberal fluid therapy within the ERAS protocol, and revealed improvements in OS with restrictive fluid therapy, but no differences were found in local recurrence [28]. One study compared early oral feeding with conventional oral feeding within ERAS protocol, and found no difference in days to RIOT after surgery [35].

Discussion

Since the concept of ERAS was proposed more than 20 years ago, these regimen has been widely applied in cardiac surgery, general surgery, neurosurgery, head and neck surgery, thoracic surgery, gynecologic surgery, urinary surgery, and orthopedic surgery. Clinical evidence has proved that ERAS can improve short-term postoperative outcomes in both cancer and non-cancer surgeries. For cancer patients, quality of life and long-term survival are the most important factor. However, whether the short-term benefits of ERAS are associated with long-term benefits in patients undergoing cancer surgeries has not yet been verified.

The results of this review showed that ERAS improved the on-time initiation and completion of RIOT after cancer surgeries. Various factors are considered when deciding to start adjuvant chemotherapy after surgery, of which, the patient’s condition is the most important one [36, 37]. ERAS improves short-term outcomes including patient conditions, so cancer patients undergoing ERAS can receive on-time and higher-rate chemotherapy after surgery. The interval from surgery to adjuvant chemotherapy is commonly 30 to 60 days; the interval in the included studies ranged from 33 days to 68 days, so the initiation or completion of RIOT is a mid-term outcome measure [38], not a short-term or long-term measure. This review showed that ERAS could not improve long-term OS or CSS in the majority of the included studies. Theoretically, improved short-term outcomes are postulated to be associated with long-term outcomes; however, the results of this review suggested that ERAS-induced improvement of mid-term oncologic outcomes was not associated with long-term survival, and no studies have compared the effects of ERAS and non-ERAS on local recurrence and metastasis until now. It was reported that the long-term prognosis after bladder cancer surgery was determined by tumor stage, presence of metastasis at surgery, and resection status [12]. ERAS might not play the pivotal role in long-term prognosis.

Adherence to ERAS is critical for short-term outcomes. Higher adherence is associated with better short-term outcomes [39, 40]. This review included 6 studies comparing long-term survival between high adherence to REAS and low adherence to ERAS [16, 22,23,24, 34], and half reported improvements in survival by high adherence, and half did not. One study reported improvements in on-time initiation of RIOT with high adherence [25]. Till now, the criteria of the adherence to ERAS have not been well defined, and the level of high adherence ranged from 67 to 85% in the included 7 studies. Higher adherence is more difficult to implement, and 70% adherence to ERAS is considered a common standard of high adherence and an achievable target in the clinic [40].

Within the ERAS protocol, restrictive fluid therapy could reduce 5-year OD and CSD in one study, while the effects on long-term survival were controversial between laparoscopic and open surgery in two studies, days to RIOT was not improved by early oral feeding compared with conventional oral feeding. Till now, studies on alteration of one single item within ERAS protocol were scarce. Furthermore, the ERAS protocol is a combination therapy, and the pre-, intra-, and postoperative items are combined together to improve postoperative outcomes. So alteration of one single item within ERAS protocol might not be so important for the oncologic and long-term outcomes. In the 26 included studies in this review, the most frequently used components of ERAS included patient education and counseling, avoidance of bowel preparation, carbohydrate loading, regional anesthesia, targeted fluid therapy, multimodal analgesia, early removal of nasogastric tubes and drainage, early oral feeding, and mobilization. However, the number of ERAS components ranged from 3 to 18 in these studies, and different numbers of ERAS components might cause different outcomes. Perioperative steroids or discharge planning were used in few studies. Therefore, the standard ERAS protocol should be used for each type of cancer surgery in accordance with the ERAS protocols in the ERAS interactive audit system, so that the oncologic and long-term outcomes under a defined framework can be fully assessed.

There are some limitations in this systematic review. First, tumor entities and surgical procedures were quite different; although in each study the results were comparable between groups, the results between studies were not comparable. Second, ERAS protocols and the follow-up time in these included trials were not uniform, so that meta-analysis could not be conducted. Third, DFS is a most important endpoint in oncologic studies, but only few studies reported the effect of ERAS on long-term DFS; regardless of the fact that ERAS could improve RIOT after surgery, the long-term oncologic outcomes after ERAS were still unclear. Fourth, the majority of the included studies were of cohort studies, and large RCTs are needed to verify the effects of the ERAS protocol on oncologic and long-term outcomes in the future.

Conclusions

This systematic review identified 26 studies with variable patient populations, cancer surgeries, and ERAS protocol implementation. Our results showed that ERAS protocols in cancer surgeries can improve the on-time initiation and completion of adjuvant chemotherapy after surgery, and high adherence to ERAS lead to better outcomes than low adherence. Based on the current evidence, it is difficult to determine whether the ERAS protocol is associated with recurrence or metastasis and long-term survival. Future efforts should be directed towards the application of a standard ERAS protocol in each type of cancer surgery and evaluation of its impact using larger, comparative multi-center studies at high- and low-volume medical centers.