Introduction
Pancreas and liver malignancies are common tumours with increasing incidence and poor prognosis. Five-year survival is 9% for all stages of pancreas malignancies and 18% for liver malignancies [
1]. To improve this unfavourable outcome, multidisciplinary approach including neo- or adjuvant chemotherapy combined with surgical resection has become the best treatment to offer long-term disease-free (DFS) and overall survival (OS).
The ESPAC-3 trial showed that the most important factor for long-term survival in pancreas adenocarcinoma was to achieve complete cycles of adjuvant chemotherapy. However, if it is not possible to undergo full cycles, the recommended strategy is to wait for a full post-operative recovery rather than to start early without being able to finish the treatment [
2]. On the other hand, delayed chemotherapy after 12 weeks would not be associated with a decreased long-term survival for pancreatic cancer, because adjuvant chemotherapy is a prognostic factor by itself, so it should be offered even later [
3]. For colorectal cancer and its liver metastases, it is well demonstrated that adjuvant chemotherapy should be initiated within 6 to 8 post-operative weeks to offer the best long-term outcome [
4‐
6]. Therefore, the timing for adjuvant chemotherapy is one of the key elements in patients with hepatobiliary and pancreatic malignancies. For this reason, recovery after surgery should be optimal to allow chemotherapy beginning as soon as the patients are fit enough.
Enhanced Recovery After Surgery (ERAS) pathway has been developed to reduce the negative effect of the surgical stress. Numerous meta-analyses have shown the benefits of an ERAS pathway implementation in pancreas and liver surgery [
7‐
11]. The principal advantages are a reduction in medical complications after surgery, reduced length of stay and decreased costs. Guidelines for ERAS protocol are based on these studies and applied in many hospitals worldwide [
12‐
14]. Achieving the same goals, recent studies have shown the benefits of introducing other similar pathways, especially targeting perioperative rehabilitation and more precisely pre-habilitation [
15].
The question remains whether ERAS pathways have an impact on the time to receipt of adjuvant chemotherapy. Moreover, data on the association between the compliance to ERAS and the increase of DFS and OS are scarce.
The aim of this study was to analyse the impact of ERAS compliance on the delay to adjuvant chemotherapy in patients operated for liver and pancreas malignancies.
Discussion
The results of this study confirmed the positive effect of high compliance to ERAS regarding the post-operative outcomes in patients with hepatobiliary and pancreatic malignancies. In particular, an association between high ERAS compliance and a reduction in the time to receipt of adjuvant chemotherapy was identified in the subgroup of young patients (< 65 years) whatever their comorbidities.
To our knowledge, no published study has assessed the relationship between ERAS compliance and the delay to adjuvant treatment for pancreatic and liver malignancies. It seems more likely that this delay would mainly be related to post-operative complications [
19,
20,
24].
Wu et al., in a retrospective study including more than a thousand patients with pancreas ductal adenocarcinoma, found that complications after surgery were associated with a lower probability to have adjuvant oncological treatment and longer delay to adjuvant chemotherapy (median difference of 7 days). Moreover, they also found a correlation between post-operative complications and lower survival, but no clear relationship between delayed chemotherapy and decreased survival [
19]. Petermann et al. had similar results, with lower survival related with post-operative complications after R1 resection of pancreatic head adenocarcinoma [
25]. Kamphues et al. also found the same results in patients with pancreatic head tumours [
26]. On the other hand, Murakami et al., in a retrospective study of 100 patients, concluded that post-operative complications were associated with delayed adjuvant chemotherapy for pancreatic carcinoma. They also showed evidence that early initiation of adjuvant treatment (< 20 days after surgery) was associated with a higher DFS and OS [
24].
Valle et al., in a derived study of the prospective randomized trial ESPAC-3, with almost one thousand patients with pancreatic adenocarcinoma, found that delayed adjuvant chemotherapy up to 12 weeks for patients with completed cycles of treatment was not associated with lower overall survival [
2]. In the study by Mirkin et al., comparing a delay to chemotherapy of more or less than 12 weeks, adjuvant chemotherapy was an independent prognostic factor in patients operated for pancreatic cancer, regardless of the time of initiation [
3]. Similarly, in a retrospective study of almost nine hundred patients with pancreatic adenocarcinoma, adjuvant chemotherapy was found to be an independent prognostic factor, without any negative effect of a delayed treatment after more than 12 weeks post-operatively [
20]. Finally, Nakagawa et al. also suggested that completion of adjuvant chemotherapy is a main determinant of long-term survival [
27]. Therefore, results are conflicting and it is not clear, for hepatobiliary and pancreatic surgery, whether the delay to adjuvant chemotherapy is more important than the completion of all cycles, whatever the delay between surgery and the start of chemotherapy might be. However, it seems clear that it is more important to start an adjuvant treatment in a fit patient in order to complete all cycles of chemotherapy rather than starting too early in an unfit patient who would not tolerate the full cycles. The performance status of the patient with pancreatic adenocarcinoma is one of the main points in the decision to start adjuvant chemotherapy, which offers better outcomes [
28].
In colorectal cancer, there are no studies analysing the effect of delayed chemotherapy on survival in patients with liver metastases. In a systematic review and meta-analysis, Biagi et al. concluded that delayed adjuvant chemotherapy in colorectal cancer, all stages confound, was associated with lower survival [
4]. Kang et al. assessed the feasibility of initiating adjuvant chemotherapy before hospital discharge after surgery for stage II–IV colon cancer. They found no difference in cycle completion rates of chemotherapy for the two groups (in-hospital initiation vs outpatients). On the other hand, they found no significant difference in OS for patients with initiation of chemotherapy before hospital discharge compared with the other ones, but initiation of the treatment within 6 weeks was associated with better prognosis [
5]. A systematic review and meta-analysis of outcomes in delayed adjuvant chemotherapy (> 6–8 weeks) including gastric, colorectal and pancreatic cancers highlighted that a delayed chemotherapy was associated with a decreased survival for gastric and colorectal tumours, but not clearly for pancreatic malignancies [
6].
Thus, it is recommended that adjuvant chemotherapy should be proposed for pancreatic cancer when indicated, even if delayed, and that a main point of the outcome improvement is the reduction of post-operative complications. Therefore, ERAS pathways implementation, by reducing post-operative complications, is certainly a key element to improve survival outcomes. Indeed, our study identified reduced delay to chemotherapy in young healthy and non-healthy patients. This positive effect was not observed in elderly. This might be related to the initial functional status of elderly patients that preclude in some cases the proper implementation of all ERAS items. One can argue that younger and fitter patients demonstrate a higher compliance with the entirety of recommended therapy including ERAS and multimodal oncologic therapy. Vice versa, frail or incompliant patients may have a lower compliance with both ERAS and adjuvant therapy. However, our data showed that compliance to ERAS protocol was comparable in patients < 65 years old and > 65 years old. Moreover, it was also comparable regarding the ASA score and the CCI score.
Despite similar rates of high compliers between young and old patients, we found a stronger effect in young patients, whatever the severity of their comorbidities. This could be related to a greater reduction in post-operative complications and increased opportunity to access multimodal oncologic therapies. This needs to be addressed and confirmed in future trials.
Finally, we found better compliance to ERAS items in pre-admission and pre- and intra-operative than post-operative. Reasons for low compliance remain not clearly identified, but the global effect of ERAS implementation is well demonstrated, with reduced post-operative complications (principally medical ones) and length of stay. It is thought that many other unknown factors are implied in this relationship [
29].
This study has several limitations inherited from its retrospective design and inclusion of patients with different types of cancer (small number of observations when analysed separately). Indeed, we analysed the marginal effect of compliance on a subgroup of young patients, interacted with ASA score to take into account pre-operative comorbidities. The effect of high compliance to ERAS remained significant to reduce the delay to adjuvant chemotherapy, when compared with low compliers. Thus, the results confirm that high compliance to ERAS protocol has a positive impact on complications and the delay to chemotherapy in a subgroup of young patients, and it will pave the way to further studies using strict ERAS protocol in liver and pancreas cancer. This will allow benchmarking and better comparisons between studies.
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