Cytoreductive surgery for metastatic gastrointestinal stromal tumor: a narrative review of patient selection, objectives, and options

Introduction

Gastrointestinal stromal tumors (GISTs) are one of the most common mesenchymal tumors of the gastrointestinal (GI) tract. GISTs represent 80% of all GI mesenchymal tumors, 18% of all sarcomas, and 1–2% of all GI neoplasms (1). They originate from the interstitial cells of Cajal which act as pacemaker cells of the GI tract. GISTs were previously thought to be the same entity as leiomyomas or leiomyosarcomas. The histologic feature that distinguishes GISTs from other spindle cell neoplasms of the GI tract is the expression of the CD117 antigen (trans-membrane KIT receptor tyrosine kinase) which is seen in over 95% of GISTs (2,3).

Global incidence of GIST is approximately 10–15 cases per million per year and 4–6,000 new cases are diagnosed each year in the United States (4). The true incidence is an estimate and autopsy findings suggests that small (<1 cm) GISTs are more common than previously estimated with tumors found in up to 35% of cases (5,6).

GISTs can be located anywhere in the GI tract but the stomach is the most common location (52–70%). GISTs can be found in the small intestine (20–35%), colon and rectum (5–15%), and esophagus (<5%) (4,7-9). Most patients present with symptomatic disease (75–81%), with GI bleeding, abdominal bloating, or obstruction as the most common symptoms (4). The rest are incidentally diagnosed on imaging performed for other purposes (9).

More than half of all patients with GISTs will present with localized disease and up to 15–47% patients present with metastatic disease (8,10). The most common sites of metastases are the liver and peritoneum. Lymph node metastases are very rare and are only seen in pediatric cases (11). Unlike other sarcomas, extra-abdominal metastases such as lung, bone, or brain are also rare and seen in less than 5% of patients. We present this article in accordance with the Narrative Review reporting checklist (available at https://gist.amegroups.com/article/view/10.21037/gist-22-3/rc).

Methods

A comprehensive literature search was performed using the PubMed database from February 20, 2022 to November 30, 2022. The search strategy was performed as outlined in Table 1. Key terms included in the query were as follows: “metastatic”, “advanced”, “gastrointestinal stromal tumors”, “GIST”, and “surgery”. Articles published between 1992 and 2022 were considered for inclusion. The search was limited to published clinical studies in English. Titles and abstracts were screened to identify relevant articles discussing surgical management of metastatic or advanced gastrointestinal stromal tumors. Full texts of potentially eligible studies were reviewed. Reference lists of included articles were also examined to identify additional relevant publications. Case reports, preclinical studies, and articles not focused on surgical interventions for metastatic/advanced GIST were excluded. Data on study characteristics, surgical approaches, patient outcomes, and conclusions regarding the role of surgery were extracted from the included studies for the following narrative review.

Initial treatment options for GISTS

Treatment options for patients presenting with GIST depends on the extent of the disease. Initial work up should include contrast enhanced cross sectional imaging of the chest, abdomen and pelvis. Even when localized, GISTs can grow to involve multiple organs and be considered locally advanced and/or unresectable. Patients should be evaluated by a multidisciplinary team experience in management of patients with sarcomas.

When localized and resectable with minimal morbidity, the recommendation is to resect GISTs greater than 2 cm. Management of GIST 1–2 cm is controversial and guidelines from expert groups differ in their recommendations (3,12). A complex multi-visceral resection should be avoided upfront and a multidisciplinary discussion is indicated to consider a course of preoperative imatinib in order to potentially downstage the extent of resection. General principles of surgery for resectable GISTs are to resect the tumor with negative margins, taking care to remove the lesion without perforation or rupture. Lymphadenectomy is not oncologically indicated due to low rates of lymph node metastases, except in cases with pathologically enlarged nodes on imaging, or in patients with known succinate dehydrogenase (SDH)-deficient or translocation-associated GISTs (3,13). Laparoscopic and open approaches are both feasible depending on the experience of the operator. Preoperative imatinib may also be indicated in patients who could be potentially downstaged from an open to a laparoscopic approach. Patients who undergo laparoscopic surgery for localized resectable GISTs generally have smaller gastric tumors. Meta-analysis of existing case series shows a shorter operative time, lower intraoperative blood loss, earlier postoperative recovery, shorter hospital stay, and lower rate of overall complications and recurrence, but this is reflective of patient selection (14). Although there is less robust data in this area, long term oncologic outcomes are comparable to open (15,16).

Patients with advanced GISTs are patients who have a localized unresectable primary lesion or have evidence of metastatic spread after staging workup. These patients with advanced GISTs should undergo neoadjuvant treatment. Targeted inhibitors have changed the landscape of GIST management and many patients with advanced disease can be converted to surgical candidates.

Prior to the introduction of imatinib in 2001, outcomes for patients with advanced GISTs were poor. Conventional chemotherapy was ineffective. Due to the diagnostic inaccuracy in categorizing GISTs (as unique entities from leiomyomas or leiomyosarcomas) and the small number of patients with GISTs in trials, data on responses to chemotherapy are confounded. Regimens using doxorubin, dacarbazine, ifosfamide, cisplatin, etoposide, and epirubicin have been evaluated. The reported response rates range 0–15% with median survival of approximately 10–20 months and a 5-year survival rate of 10–20% (8,17-21).

Breakthrough therapy for GIST was developed with the recognition that activating mutations in c-KIT stimulated uncontrolled cell growth and malignant transformation (22). Imatinib is a pyrimidine derivative and a tyrosine kinase inhibitor, initially developed for chronic myelogenous leukemia (CML) and acute lymphocytic leukemia (ALL). It binds to the active domain in ABL, PDGFRA, and c-KIT to inhibit tyrosine kinase activity. It was introduced as a therapy for GISTs in 2000 and obtained FDA approval in 2002. With either KIT (70–80%) or PDGFRA (10–20%) acting as the driver mutation, therapy with imatinib has revolutionized the management of GISTs (23). Compared to previous systemic therapies, there were responses in over 50% of patients with advanced GISTs who received imatinib (24). Median survival in patients with patients with advanced disease increased to 52–57 months (25,26). As such, imatinib is recommended as the first line treatment for patients with advanced GIST with KIT or PDGFR mutations.

Other therapies for GISTs include avapritinib, a tyrosine kinase inhibitor that targets mutations in the PDGFRA exon 18 D842V. Patients with PDGFR D842V mutations are treated with avapritinib in the first line setting. Sunitinib is considered the second line therapy and is a multi-targeted tyrosine kinase inhibitor, with anti-tumor and anti-angiogenic effects, which blocks KIT, VEGF 1, 2, 3, PDGFR A, B, RET, and FLT3. It was demonstrated to be efficacious in 312 patients with imatinib refractory or intolerant GIST who were randomized in a 2:1 ratio to sunitinib vs. control (27). Sunitinib demonstrated a significantly longer median time to progression (TTP) (6.8 versus 1.6 months). Other lines of therapy include regorafenib, ripretinib, as well as cabozantinib, dasatinib, everolimus, nilotinib, pazopanib, and sorafenib.

Given the efficacy of targeted inhibitors, other local treatment modalities that are considered for GI malignancies such as radiation or targeted ablation are only used in a palliative setting for advanced GISTs. Metastatic GISTs limited to the liver only are candidates for consideration of hepatic artery chemoembolization, or in specialized centers, hepatic artery infusion pumps (28,29).

Objectives of surgery for advanced GIST

Surgery should begin with a careful exploration of abdomen to identify extent of disease. The surgeon should carefully assess extent of the known tumor burden and diagnose any previously undetected peritoneal deposits. Wide margins and extended anatomic resections are not necessary and organ preservation should be considered if anatomically feasible. Care should be taken to avoid tumor spillage especially if the tumor was initially locally advanced so that peritoneal seeding can be prevented. Minimally invasive approaches can be considered based on surgeon experience and expertise.

Outcomes of surgery for advanced GIST prior to targeted therapy

Patients with advanced GISTs had little effective options prior to targeted therapy and aggressive surgery including cytoreduction of metastatic disease was performed in an attempt to improve outcomes. Data from these carefully selected cohorts during this period supports the concept that cytoreductive surgery can impact survival if an R0/R1 surgery could be achieved.

Ng et al. reported a series of 191 patients treated at the MD Anderson Cancer Center from 1957–1987 with GI “leiomyosarcomas”, which were most likely GISTs under modern categorization. There were 168 patients who underwent surgery (30). Approximately half had localized resectable disease and the rest were locally advanced or metastatic. Patients who had locally advanced (contiguous organ involvement) or metastatic disease had median overall survival (OS) of 19–28 months after surgery. Patients who had complete resection had an OS of 48 months compared to those who underwent incomplete resection (median OS 21 months) or those who had complete resection but had tumor rupture (median OS 17 months). Patients who had a complete resection (including those who had localized resectable disease) had a median TTP of approximately 30 months. Multivariate regression analysis showed that the completeness of surgery was the primary determinant of OS. They found that outcomes for even patients with multi-visceral involvement or peritoneal implants were not significantly different from patients with localized lesions as long as all tumor was resected.

Gold et al. reported a series of 119 patients treated at the Memorial Sloan Kettering Cancer Center (MSKCC) with metastatic GIST from 1981–1998 (21). These patients were diagnosed 2 years prior to the introduction of imatinib and had retrospective pathologic re-review, confirming a diagnosis of GIST. Of the 199 patients with metastatic GIST, 81 (68%) underwent surgery. The median OS of all patients was 19 months with a 41% 2-year survival and a 25% 5-year survival. Those who were able to undergo surgery had an improvement in median OS to 27 months, a 53% 2-year survival, and a 33% 5-year survival. Those who were able to receive an R0 resection had better outcomes with median OS of 61 months, an 84% 2-year survival, and a 52% 5-year survival. The degree of benefit correlated with the degree of debulking that was performed. In this series, there was even a benefit seen in those who received an R2 resection, compared to those who did not receive any resection at all.

In the era without effective adjuvant therapy, surgical cytoreduction was able to improve the median survival of patients from 10–20 to 48–61 months when a complete resection was able to be performed.

Outcomes of patients with advanced GIST treated with imatinib

The use of targeted therapy in GISTs, specifically imatinib, has revolutionized the management of advanced GIST. Patients are able to enjoy prolonged disease stabilization compared to pre-imatinib era. The phase II multi-centered study B2222 was the first multi-centered study providing data on the response rate of advanced GIST to treatment with imatinib (24). This was an open-label study which randomized 147 patients with advanced GIST to either 400 or 600 mg of imatinib. There was a response to treatment in 54% of patients, stable disease in 28%, and progression in 14%. Longer follow up of this cohort showed that there were responses in 68% (25). There was a median TTP of 24 months with a median OS of 57 months. There were no differences in outcomes based on the two doses. Two other larger studies confirmed this. SWOG-S0033 and EORTC-ISG-AGITG, enrolling 746 and 946 patients respectively, compared 400 vs. 800 mg of imatinib and did not see a difference in the initial higher dosing of imatinib (31,32). They reported response rates of 45–52%, disease stabilization in 22–32%, and disease progression in 10–16%. Median TTP in SWOG-S0033 was 18–20 months with a median OS of 51–55 months. Median TTP in EORTC-ISG-AGITG study was approximately 21–24 months and median OS was not reached at 30 months. These results in patients with advanced GISTs on imatinib therapy were a significant improvement from previous lines of systemic therapies which had median OS of 10–20 months (17-19).

Outcomes for patients with advanced GIST treated with imatinib and surgery

While patients treated with imatinib benefit from a prolonged period of disease stability, it is not curative, and resistance eventually develops. Time to best response after initiation of imatinib therapy has been reported to be approximately 2.7–3.5 months with a median duration of response of 29 months (31,32). After this period, resistance can develop, and progression of disease occurs. Evaluation of resistance mechanisms to targeted inhibitors demonstrate a substantial heterogeneity of resistance mutations within and between metastases from individual patients (33). Cytoreductive surgery could potentially offer a disease-free interval, reduce disease burden, and decrease risk of resistance by exposing fewer cells to imatinib. Previous era of surgical resections without imatinib have demonstrated effective disease management after cytoreduction without effective systemic therapy with careful patient selection. Can a combination of both approaches, with imatinib and surgery, further improve outcomes in patients with advanced GISTs?

With improvements in OS of patients on imatinib, the focus of these studies has shifted from evaluating OS, to prolonging time to recurrence or TTP, if unable to completely cytoreduce. Data on outcomes after cytoreductive surgery for advanced GIST in conjunction with perioperative imatinib are limited as they are predominantly retrospective case series. An overview of these studies is summarized in Table 2 [adapted from Kikuchi et al. (34)]. The most robust data comes from multi-centered retrospective case series. There are no large-scale randomized trials investigating the therapeutic relevance of surgery in patients with advanced GISTs due to the relatively limited disease incidence.

A study from the EORTC-Soft Tissue/Bone Sarcoma Group describes 239 patients with advanced GISTs on imatinib for at least 3 months who underwent surgery (46). There were 189 (79%) complete cytoreductions and 50 (21%) patients with residual disease after surgery. Patients were classified by progressive vs. non-progressive disease at the time of surgery. Patients who had non-progressive disease and received a complete cytoreduction had the best outcomes. The median PFS and OS were not reached for this group. If the cytoreduction was incomplete, the median PFS was 22.8 months, and median OS was 48 months. Patients who had progressive disease had more rapid recurrence of disease. If they were able to receive a complete cytoreduction, the median PFS was 13.2 months and median OS was 45.6 months. If they were unable to receive a complete cytoreduction, median PFS was 7.2 months, and median OS was 18 months. The 30 day post-operative mortality rate was 0% and the post-operative morbidity was reported at 8.9%, with these patients needing re-operation, endoscopic intervention, prolonged hospitalization or wound care. The data supports the concept that an aggressive cytoreduction can be safely performed in patients with advanced GIST with a durable response. The durability of disease control from surgery was better in patients who had imatinib responsive disease and received a complete cytoreduction. The authors recommend consideration of surgery during remission rather than progression.

Another large series incorporating patients from seven major cancer centers in the United States and Canada reported on 158 patients with advanced GISTs undergoing surgery (47). The authors break the groups down by locally advanced (n=87) vs. recurrent/metastatic GISTs (n=71). When the authors looked at patients with recurrent/metastatic GIST who received pre-operative targeted therapy, non-progressive (responsive or stable disease) was associated with an improved recurrence-free survival (HR 3.90, P=0.03) and OS (HR 7.1, P=0.02). Median PFS was 71.9 months in patients with non-progressive disease vs. 13.5 months in patients with progressive disease. Median OS was not reached in patients with non-progressive disease vs. 17.1 months for patients with progressive disease. While this series had a comparatively lower rate of treatment with targeted inhibitors (only 21% of patients with locally advanced GISTs and 38% of patients with recurrent/metastatic disease), the patterns are comparable to other studies. The post-operative mortality rate was 1.1% and the rate of post-operative morbidity (Clavien-Dindo Grade 3 or above) was 10.3%. The receipt of neoadjuvant therapy was not associated with the rate of post-operative complications. Similar to other studies, improvement in outcomes after surgery were significant if patients were imatinib-responsive prior to surgery.

The largest series of patients with advanced GISTs undergoing surgery (323 patients) is from the combined database of the Brigham and Women’s Hospital/Dana Farber Cancer Institute and Memorial Sloan Kettering Cancer Center (43). This series included patients treated with both imatinib and sunitinib. They further classify non-progressive disease into stable disease in 100 patients (25%) vs. responsive disease in 64 patients (16%). Progressive disease was further classified into unifocal progression in 132 patients (33%) vs. multifocal progression in 104 patients (26%). In patients treated with imatinib, median PFS after surgery was 36 months in responsive disease, 30 months in stable disease, 11 months in patients with focal progression, and 6 months in patients with multifocal progression. The median OS in patients treated with imatinib was not reached in patients with responsive disease, 110 months in stable disease, 59 months in patients with focal progression, and 24 months in patients with multifocal progression. In this population, the post-operative mortality was 1.8% and the morbidity (Clavien-Dindo Grade 3 or higher) was 18%. Those patients with responsive or stable disease on imatinib who underwent metastasectomy showed significantly improved outcomes compared to those with progressive disease. Like the studies cited previously, patients with responsive disease receive the greatest benefit from surgery. Among patients with progressive disease, patients with unifocal progression had better outcomes than patients with generalized progression. The authors note that while a median PFS of 11 months for patients with unifocal progression is not ideal, this outcome is still better compared to the alternative 2^nd line therapy. Treatment with sunitinib only provides a median PFS of 6.8 months (27). Disease response did not correlate with outcomes in patients who received sunitinib, likely because this is a population heavily pre-treated with both systemic therapy and surgery by the time of assessment.

These studies and many other smaller studies hint at long-term survival after complete cytoreduction with combination therapy of imatinib and surgery in patients who are responding to treatment. However, a randomized controlled trial, EORTC/STBSG-SURGIST (NCT00956072), attempting to addresses this question closed early due to low accrual. This multi-centered European trial closed after accruing only 12 patients, indicating the difficulty in randomizing a major intervention such as surgery in a rare disease such as GIST.

The ChiCTR-TRC-00000244 multi-centered study from China which also closed early due to poor accrual, was able to accrue 41 patients to the trial prior to closure (48). All patients had to have disease that was either responsive or stable on imatinib for at least 3–12 months and all patients had to have resectable residual disease prior to randomization. Patients (n=19, 46%) who underwent surgery while responsive to imatinib were compared to patients who remained on imatinib therapy only (n=22, 54%). The median PFS and OS were not reached for patients in the surgical arm vs. 32 and 49 months respectively for the imatinib only arm. At 2 years, 88.4% of patients in the surgery arm had progression free survival vs. 57.7% without surgery. There were no post-operative mortalities and while the types of post-operative morbidities were not classified, the all-cause morbidity rate was 21% including bleeding, infection, hepatic/renal insufficiency, and delayed gastric emptying. They were able to demonstrate a significant improvement in median OS in patients who received surgery, even with a limited cohort. Another study from China by Xia et al. report on a single-centered randomized control trial of 39 patients with recurrent GISTs and liver only metastases who were randomized to either 6 months of imatinib followed by surgery in 19 patients (49%) or imatinib only in 20 patients (51%) (49). The 1-year OS was 100% in patients who received surgery vs. 85% receiving imatinib only. The 2-year OS was 89.5% after surgery and 60% without surgery. There was a significant difference in OS between the two groups, favoring the surgery group (P=0.03). There were no post-operative mortalities and the post-operative morbidity rate was 15.8%. The disease burden in these cohorts have limited applicability compared to existing case series: one study had no patients with liver metastases and the other study had liver limited metastases. While underpowered, these studies provide a signal that there is a benefit for cytoreduction and highlights a need for additional studies to address this question.

These studies further support the concept that cytoreductive surgery can impact outcomes when a complete cytoreduction can be performed safely, echoing results obtained after surgery in the pre-imatinib era. The low post-operative mortality rate in patients undergoing major surgery with multi-visceral resection shows that these patients can be addressed with aggressive cytoreduction, leading to improved outcomes. When stratified by response to imatinib, patients who had responsive disease benefitted the most from aggressive surgery.

Outcomes after surgery for patients with advanced GIST treated with second-line tyrosine kinase inhibitors and beyond

Surgical management of patients after treatment with sunitinib was more aggressively pursued prior to the approval of regorafenib as a third line therapy in advanced GISTs (50). There is conflicting data on the survival advantage from surgery. Patients treated in this advanced phase of disease have complex and heterogeneous disease biology that has escaped first line imatinib and second line sunitinib treatment. Raut et al. report on the largest series of patients (n=50) who underwent surgery after median 6.7 months of sunitinib (44). They discuss the feasibility of surgery after extensive treatments. However, this was at the cost of high rates of incomplete resections (n=25, 50%). The post-operative mortality rate was 2% and there was a high rate of post-operative morbidities (n=27, 54%) which were driven by a history of major prior surgeries in 40 (80%) patients. Median PFS after cytoreductive surgery on sunitinib was shorter 5.8 months compared to PFS after surgery on imatinib. The median OS, at 16.4 months was likewise shorter. Unlike treatment response to imatinib, there were no differences in PFS or OS based on responses to sunitinib. A complete cytoreduction was possible only in 50% of cases and this did not correlate with treatment response to sunitinib. Yeh et al. report on a case series of 26 patients who had local progression on sunitinib after a median of 6.2 months on therapy (45). Here the rate of previous surgeries (n=19, 73.1%) was comparable. The complication rate was lower at 15.3%, but only major complications were counted. Median PFS was 5.2 months and median OS was 20 months. Other smaller case series, reporting 4 and 2 cases each, support the feasibility of surgery after sunitinib but these efforts were driven by a lack of efficacious third line options (51,52). The use of regorafenib resulted in comparable median PFS 4.8 (vs. 0.9 months control, HR 0.27) (50). With favorable disease control rates of 52.6% on regorafenib and the availability of other lines of treatment as well as the option to re-challenge with imatinib (53), surgery is now only considered in very limited cases.

There is even less data available on the surgical outcomes for patients with advanced GISTs treated with newer tyrosine kinase inhibitors such as ripretinib and avapritnib. The survival benefit of aggressive surgery in the third line therapy setting is unclear. However the response status to therapy remains an important factor in decision making. Careful patient selection after multi-disciplinary discussion, taking into account individual performance status, volume of disease, location of disease, impact of critical anatomic structures, and likelihood of complete resection is pivotal.

Predictors of morbidity after cytoreductive surgery for advanced GIST

Advances in surgery and peri-operative care along with improve patient selection have made it possible to perform advanced and aggressive surgeries such as cytoreduction for advanced GIST. The studies above demonstrate a very limited and respectable mortality rate after major abdominal surgery. The rate of reported morbidity after such cases is variable due to international variability in reporting and categorization of post-operative complications. However a major abdominal surgery which can involve technically challenging components with multi-visceral resection has a high potential for post-operative complications. Standard surgical risk-calculators often underestimate the morbidity of complex oncologic surgeries such as cytoreduction for advanced GISTs. A surgical complexity score specific to advanced GIST may further help identify patients who are at higher risk of morbidities which could help in further pre-operative risk stratification and optimal treatment planning (54).

The future of surgery for advanced GIST: oligoprogression?

To further decrease the risk of morbidity from a cytoreductive surgery, but still maintain the benefits of surgery for patients with advanced GIST, alternative, more limited approaches could be considered. In patients who are otherwise responding to systemic therapy, with oligoprogression, an extensive surgery to remove all disease may not be necessary, but rather a limited procedure to remove the focus of progressive disease. Advantages are that a limited surgical resection could address the resistant foci while the targeted therapy provides control to the remaining responsive disease. Limitations are that the concept is difficult to methodically categorize and describe prospectively. Patients with multiple lesions with varying degrees of response to therapy are challenging to compare. Additional disadvantage of limited cytoreduction is subjecting a patient to the risk inherent in any surgery and providing an “incomplete” cytoreduction that leaves behind remaining disease which will eventually develop resistance. In patients who have repeat or serial debulking surgery rather than complete cytoreduction, there was unfortunately no improvement in event-free survival, however this case series has limited comparisons as this was reported in patients with SDH-mutant GIST, a rare subtype with little effective systemic therapies (55). Most patients with advanced GIST benefit from the systemic control such that limited surgery, or other local approaches, can be considered for progressive foci. This type of approach is being increasingly utilized in melanoma where effective immunotherapies are providing sufficient disease control in patients with stage 4 disease such that surgery and other local treatments such as radiation and ablation becomes an effective adjuncts (56). In addressing GIST, a disease with a significantly lower prevalence, prospective collaborative international group efforts such as that modeled by the Transatlantic Australasian Retroperitoneal Sarcoma Working Group will further shed light on this topic (57,58).

Conclusions

Surgery holds the potential to provide the patient a disease-free interval, decrease the burden of disease, and reduce likelihood of developing resistant mutations to prolong durable disease control. The role of surgery in management of advanced GIST has significantly shifted since the development of imatinib. As targeted inhibitors develop in sophistication, the need for surgical intervention and determination of the extent of surgical intervention will continue to evolve and will continually need to be assessed.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Claudia Valverde, Nadia Hindi) for the series “Management of Gastrointestinal Stromal Tumors” published in Gastrointestinal Stromal Tumor. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://gist.amegroups.com/article/view/10.21037/gist-22-3/rc

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gist.amegroups.com/article/view/10.21037/gist-22-3/coif). The series “Management of Gastrointestinal Stromal Tumors” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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