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Review

Selection of Chemotherapy in Advanced Poorly Differentiated Extra-Pulmonary Neuroendocrine Carcinoma

by
Jamie M. J. Weaver
1,2,
Richard A. Hubner
1,
Juan W. Valle
1,2 and
Mairead G. McNamara
1,2,*
1
The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
2
Division of Cancer Sciences, School of Medical Sciences, University of Manchester, Manchester M20 4BX, UK
*
Author to whom correspondence should be addressed.
Cancers 2023, 15(20), 4951; https://doi.org/10.3390/cancers15204951
Submission received: 9 June 2023 / Revised: 2 October 2023 / Accepted: 2 October 2023 / Published: 11 October 2023
(This article belongs to the Special Issue Advanced Neuroendocrine Tumors)
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Abstract

:

Simple Summary

Extra-pulmonary poorly differentiated neuroendocrine carcinoma is a rare tumour type with a limited evidence base for its treatment. Recent work has helped to clarify the optimum first-line chemotherapy regimen. However, in the second-line setting, data remain sparse. A more personalised approach is warranted, given the heterogeneity of this disease, and emerging translational approaches focused on mouse models, organoids, and comprehensive genomic profiling may guide future trial design.

Abstract

Extra-pulmonary poorly differentiated neuroendocrine carcinoma is rare, and evidence for treatment has been limited. In this article, the evidence behind the cytotoxic chemotherapy choices used for metastatic or unresectable EP-PD-NEC is reviewed. In the first-line setting, etoposide and platinum chemotherapy or irinotecan and platinum have been demonstrated to be equivalent in a large phase III trial. Questions remain regarding the optimal number of cycles, mode of delivery, and the precise definition of platinum resistance in this setting. In the second-line setting, FOLFIRI has emerged as an option, with randomized phase 2 trials demonstrating modest, but significant, response rates. Beyond this, data are extremely limited, and several regimens have been used. Heterogeneity in biological behaviour is a major barrier to optimal EP-PD-NEC management. Available data support the potential role of the Ki-67 index as a predictive biomarker for chemotherapy response. A more personalised approach to management in future studies will be essential, and comprehensive multi-omic approaches are required to understand tumour somatic genetic changes in relation to their effects on the surrounding microenvironment.

1. Introduction

Extra-pulmonary poorly differentiated neuroendocrine carcinoma (EP-PD-NEC) is a rare disease with a poor prognosis. Neuroendocrine neoplasms form a continuum of biology ranging from well-differentiated, slowly proliferating lesions—neuroendocrine tumours (NETs)—to poorly differentiated, faster proliferating large or small cell neuroendocrine carcinomas (NECs) [1]. Poorly differentiated (PD) tumours are characterised by the presence of significant nuclear atypia patches of necrosis and grossly distorted tissue architecture. The majority of EP-PD-NECs arise in the gastrointestinal tract, but they can arise from a variety of other organs, with up to a third having no identifiable primary site [2]. In addition, most cases present at an advanced disease stage where cure is not an option, with a median prognosis of usually less than 1 year [3].
The genetic or epigenetic changes that drive this biology have begun to be determined through detailed genomic sequencing work [4]. Higher-grade poorly differentiated tumours more commonly harbour TP53 mutations and RB1 loss, in keeping with those seen within pulmonary small cell carcinoma [5]. Recurrent mutations in many genes have been identified, but, as of yet, no highly recurrent targetable driver genes have been identified [6,7]. Rare instances of druggable targets are emerging, such as microsatellite instability, Neurotrophic tyrosine receptor kinase (NTRK), and v-raf murine sarcoma viral oncogene homolog B1 (BRAF), which are enriched in NECs originating from the colon [4]. Nonetheless, cytotoxic chemotherapy currently remains the mainstay of clinical management in the metastatic setting, except in rare circumstances where tumour-agnostic therapies are indicated, as above.
In high-grade neuroendocrine neoplasms, patient prognosis is closely linked to morphological findings upon pathological assessment, including the degree of differentiation and large-cell or small-cell morphology within the poorly differentiated cohort [8]. Patients with poorly differentiated carcinomas with increased proliferation rates have significantly worse outcomes than those with well-differentiated tumours with similar proliferation rates [9]. The assessment of neuroendocrine neoplasm morphology is complex, and given the prognostic and predictive implications, centralized specialist pathology review is essential (Figure 1). It is important to note that prognosis has also been associated with the proliferation rate, measured either by mitotic index or by Ki-67 staining; cases with higher Ki-67 indices have worse overall survival [10]. A higher Ki-67 index has also been shown to be predictive of the response to therapy. A cut-off of the Ki-67 index of >55% has been suggested to identify EP-PD-NEC cases with a better response to first-line therapy [10]. However, in a recent meta-analysis, this relationship was not present in the second-line setting [11]. Furthermore, a recent, detailed study of pancreatic NEN after expert pathologist assessment to separate G3 NETs from NECs also did not show a Ki67 index > 55% to be predictive of the response to platinum-based therapy [6] Further studies are required to better characterise this association in EP-PD-NEC [12].
Given its rarity and biological complexity, data to guide the use of systemic anti-cancer therapy in EP-PD-NEC were previously limited mostly to retrospective case series or single arm prospective phase 2 trials [11]. Recently, however, randomised clinical trial data have begun to emerge, with the presentation of the TOPIC-NEC, BEVANEC, and NET-02 trials demonstrating the feasibility of clinical trials in this disease group when delivered through large specialist networks [3,13,14]. In this review, the current evidence base for the use of cytotoxic chemotherapy in advanced EP-PD-NEC will be explored, with a focus on a proposed management algorithm (Figure 1). The roles of immunotherapy and targeted agents have been discussed in detail in several recent reviews, and they will not be explored in detail in this current manuscript [4].
Cancers 15 04951 g001
Figure 1. A suggested treatment algorithm. Choice of regimen should also consider patient factors, such as comorbidities and other organ dysfunction. The use of first-line regimen re-challenge with relapse between 3 and 6 months post-first-line should be based on the initial depth of response and the patient’s tolerance of the first-line regimen. TemCap, temozolomide and capecitabine; FOLFIRI, 5-Fluorouracil and irinotecan; NALIRI, nanoliposomal irinotecan and 5-Fluorouracil; BSC, best supportive care; FOLFOX, 5-Flurouracil and oxaliplatin; FL, first line; PS, ECOG performance status [10,15,16,17]. * Depth of response and tolerance to first-line therapy along with comorbidities are important considerations in deciding on re-challenge.
Figure 1. A suggested treatment algorithm. Choice of regimen should also consider patient factors, such as comorbidities and other organ dysfunction. The use of first-line regimen re-challenge with relapse between 3 and 6 months post-first-line should be based on the initial depth of response and the patient’s tolerance of the first-line regimen. TemCap, temozolomide and capecitabine; FOLFIRI, 5-Fluorouracil and irinotecan; NALIRI, nanoliposomal irinotecan and 5-Fluorouracil; BSC, best supportive care; FOLFOX, 5-Flurouracil and oxaliplatin; FL, first line; PS, ECOG performance status [10,15,16,17]. * Depth of response and tolerance to first-line therapy along with comorbidities are important considerations in deciding on re-challenge.
Cancers 15 04951 g001

2. First-Line Systemic Therapy Options for Patients with Advanced EP-PD-NEC

A choice of first-line therapy in patients with EP-PD-NEC is a platinum, either carboplatin or cisplatin, in combination with etoposide [18]. This was first proposed due to the perceived similarity of EP-PD-NECs and small cell carcinomas of the lung, which have an extensive evidence base. The efficacy of this treatment was first demonstrated in a cohort of 18 tumours, defined by histopathological morphology criteria as EP-PD-NEC-NEC [19]. Responses were seen in a total of 12/18 (67%) patients, with a complete response (CR) in 3 cases. A subsequent study demonstrated a response rate of 41.5% (17/41) with the cisplatin/etoposide combination using identical dosing [20]. More recent larger cohort studies have confirmed the efficacy of this first-line regimen; Sorbye et al. reported a response rate of 28% amongst 148 patients with non-small cell EP-PD-NECs, with a progression-free survival (PFS) of 4 months and OS of 11 months [10]. The same study reported an additional 118 patients with small cell morphology, but no difference was observed in response rate or OS in this population. Yamaguchi et al. reported a response rate of 28% amongst 46 patients treated with EP in a Japanese population in the first-line advanced setting, with an OS of only 7.3 months, and Frizziero et al. reported a disease control rate for platinum/etoposide of 74.5% with a median OS of 11.5 months [21,22].
Guidelines support the use of cisplatin or carboplatin in the first-line advanced setting for EP-PD-NEC in combination with intravenous or oral etoposide [23,24]. In the Nordic-NEC database, no difference was observed in ORR or OS between patients treated with carboplatin and cisplatin [10]. In the only randomised phase 3 trial to date, TOPIC-NEC, cisplatin was used in both arms, and in a recent survey of 75 oncologists treating EP-PD-NEC, there was equipoise, with 52% favouring cisplatin [25]. In small cell lung cancer, a meta-analysis of four trials, including a total of 663 patients (453 extensive stage-SCLC), confirmed that cisplatin and carboplatin provided equivalent benefits, with no difference seen in the Objective Response Rate (ORR) (67% vs. 66%, cisplatin vs. carboplatin) and no difference in OS [17]. Myelotoxicity was increased with carboplatin; in particular, thrombocytopenia, nephrotoxity, ototoxity, emesis, and alopecia were increased with cisplatin. There was no toxicity-associated mortality difference between the two agents. An additional single retrospective study has compared the two platinum agents in 263 patients with EP-PD-NEC in the first-line advanced setting, suggesting carboplatin was associated with worse OS in a Canadian population. This association remained significant in multivariable analysis, while controlling for disease stage (Hazard Ratio (HR) 1.40; 95% Confidence Interval (CI) 1.02–1.92); however, the retrospective nature of the study means that bias in patient selection is likely [26]. The use of cisplatin or carboplatin in the first-line setting should be individualized to the patient, with consideration given to age, renal function, and performance status. In SCLC, it has been demonstrated that there is no benefit in survival with the use of the intravenous (IV) route versus the oral route for etoposide [27]. In EP-NEC, two retrospective studies have addressed this question. In 236 patients from the NORDIC-NEC register focusing on gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs), no difference was observed between IV etoposide and oral etoposide, although only 33 patients received the oral formulation [28]. Similarly, in 113 patients with GEP-NEC, Frizziero et al. showed no difference between OS and ORR between oral and IV administration, despite a large numerical difference in OS (8.9 vs. 12.1 months, respectively) [21]. Given documented patient preferences for oral regimens, oral etoposide in some cases may be the more optimal route of delivery [29].
Alternative regimens to carboplatin/etoposide in the first-line advanced setting are advocated by some guidelines. A recent phase 3 trial run across 50 centres in Japan compared cisplatin (80 mg/m2) and etoposide (100 mg/m2 D1, 2 and 3) given in 3-weekly cycles with irinotecan (60 mg/m2 D1, 8 and 15) and cisplatin (60 mg/m2, D1) given every four weeks [3]. In total, 170 patients with digestive NEC were randomised, 50 percent of which were small cell carcinomas and nearly 40% of which were oesophageal or gastric in origin. Central pathology review was mandated and performed on all patient tumours, where blocks were available (168/170); 9.5% of patients were reclassified. Treatment was continued until progression or intolerable toxicity, with a median of 4.5 cycles given in each arm. Response rates were the same with the two regimens (etoposide/cisplatin vs. irinotecan/cisplatin, 54.5% vs. 52.5%, respectively). Median OS was not significantly different between arms (etoposide/cisplatin vs. irinotecan/cisplatin, 12.3 months vs. 10.5 months, respectively). There was no difference in survival between sub-groups, except for a possible benefit for etoposide/cisplatin within patients with pancreatic PD-NECs, though numbers in this group were small (n = 23). There was an excess of bone marrow toxicity in the etoposide/cisplatin group, with significantly higher rates of febrile neutropenia. However, with the introduction of primary prophylaxis with granulocyte-colony stimulating factor (G-CSF), this was mitigated. The only treatment-related death occurred in the irinotecan/cisplatin arm. This trial therefore provides support for the current standard choice of etoposide/cisplatin in the first-line advanced setting, with irinotecan/cisplatin being an acceptable alternative.
Consensus on the number of cycles is limited across guidelines. Data from SCLC support the use of four cycles only with a single small phase 3 trial, with 46 ES-SCLC patients showing no benefit to extending treatment to six cycles vs. four cycles [30]. This has been confirmed by a large single-site United-Kingdom-based retrospective study that found no difference in OS between those patients treated with four cycles and those treated with six [31]. Therefore, four cycles of etoposide/cisplatin may be an option for EP-PD-NEC also. Nonetheless, given data specific to EP-PD-NEC are not available, there remains a need for an expert consensus view on this topic [25].
Though response rates to first-line platinum doublets are high, PFS is short, as discussed above, and alternative regimens are being explored. A recent trial (NCT02595424) has investigated the efficacy of temozolomide and capecitabine versus carboplatin etoposide (EP) as a first-line treatment [32]. Both regimens provided similar outcomes, with low response rates of 9% and 10%, respectively. The trial included both G3 NEC and NETs, with only 57 percent of tumours being poorly differentiated, and a relatively low overall Ki67 index of 48% in the TemCap arm and 60% in the EP arm. Further details on response rates by sub-group will be important to better understand the clinical relevance of these findings.
Given the limited response rates to first-line doublet therapy, triplet therapies have been explored. In a small retrospective study, a triplet regimen of 5-flourouracil, irinotecan, and oxaliplatin has shown an ORR of 46% [33]. Only eight patients in this study were treated in the first-line setting, and a detailed breakdown of the sub-group ORR was not available. The prospective FOLFIRINEC trial comparing Folfirionx to first-line EP chemotherapy will clarify the role of this regimen [34]. A triplet regimen of paclitaxel, etoposide, and platinum therapy demonstrated an ORR of 53% in a single arm study comparable to doublet therapy alone; therefore, this regimen has not been pursued further [35].

3. Second-Line Treatment for EP-PD-NEC in the Advanced Setting

Until recently, consensus for second-line treatment was unclear in this setting. The recent presentation of the prospective BEVANCEC (Bevaciuzumab added to FOLFIRI) and NET-02 (liposomal irinotecan with 5-flurouracil versus Docetaxel) randomised phase 2 trials has helped to somewhat clarify the options; however, definitive phase 3 data are awaited [13,14]. Overall, a relatively small proportion of patients with advanced EP-PD-NEC receive second-line treatment [21]. This is likely due in part to the aggressive nature of the disease and the limited evidence of efficacy of second-line regimens. More robust prospective data are therefore needed.

3.1. Re-Challenge in the Second-Line Setting

When deciding on treatment choice in this setting in patients who are fit for second-line therapy, it is important first to determine whether resistance to platinum therapy has developed. As with SCLC, time cut-offs are implemented to make this decision. A recent consensus from 75 NET specialists found the favoured re-challenge would be with carboplatin/etoposide if progression occurred after 6 months [25]. No study has looked prospectively at this question, but in two retrospective case series, response rates to second-line platinum re-challenge were 17% and 31%, though with small numbers in each study [21,22]. Evidence for irinotecan/platinum in the second-line re-challenge setting is extremely limited, with five cases reported in Yamaguchi et al. with a response rate of 40% (n = 2), suggesting it may be a suitable alternative to etoposide/platinum while acknowledging the small numbers of patients included [22].
In patients with SCLC of the lung, phase 3 randomised controlled trial (RCT) evidence supports re-challenge if there is progression beyond 3 months. Carboplatin and etoposide re-challenge was compared to topotecan monotherapy in patients who had relapsed beyond 90 days [36]. In a multivariable analysis of factors potentially associated with PFS, treatment-free interval (TFI) (90–180 days versus > 180 days) was not a significant factor. Hadoux et al. conducted a retrospective multicentre study of EP-PD-NEC identifying 94 patients with relapse beyond 90 days [37]. Patients who received a re-challenge had an improved OS compared to those who did not, with no reduction of benefit in those re-challenged between 90 and 180 days when compared to those re-challenged beyond 180 days (12 vs. 5.9 months, p = 0.043). However, these data did include thoracic NEC cases; therefore, the implications for EP-PD-NEC remain unclear. Larger case series, or, preferably, prospective studies, of patients with EP-PD-NECs will be required to determine if patients with a shorter TFI may also benefit from re-challenge and, in particular, if this applies across the proliferation and morphological spectrum of this disease.
For patients with EP-PD-NEC relapsing with platinum resistance, the evidence base for second-line options is limited to retrospective case series and, more recently, phase 2 trials. A meta-analysis of the available literature in the second-line advanced setting identified a total of 15 different regimens used across 19 studies of EP-PD-NEC [11]. Given the poor prognosis of patients with platinum-resistant EP-PD-NEC, it is essential that the benefits of any regimen are always weighed against the toxicities, and consideration should always be given to the best supportive care as an appropriate approach, particularly in those patients with poor PS, to maximise patient quality of life.

3.2. Single-Agent Chemotherapy in the Second-Line Setting

The regimens used in the second-line clinical setting cover a variety of different cytotoxic chemotherapy agents, with different targets that have been used as monotherapy or in doublets. The topoisomerase I inhibitors, topotecan and irinotecan, have both been assessed as monotherapies in several retrospective studies, including in patients with an EP-PD-NEC diagnosis. However, overall efficacy has been limited. In one retrospective assessment of topotecan in 30 patients, 2 (7%) had a partial response, whilst in a study of 22 patients, the ORR was 0% [38,39]. This response rate is similar to that seen with irinotecan monotherapy in this setting, with only 5 of 21 patients having a partial response in a recent retrospective analysis [22]. Though low, these rates are broadly comparable to the response rate seen in the registration phase 3 trial in SCLC of single-agent topotecan in the second-line advanced setting, where ORR was 7% (5 of 71). Despite this poor ORR, a near doubling of OS was observed [40]. Nonetheless, monotherapy with topoisomerase I inhibitors is not recommended in international guidelines for the treatment of patients with EP-PD-NEC [18]. Amrubicin, a topoisomerase II inhibitor, has also been trialled in several small case series (12–16 patients) in EP-PD-NEC at doses between 30 and 45 mg/m2. Response rates have been better than that seen with single-agent topotecan, with RRs ranging between 6.3% and 50% and PFS between 2 and 6 months [15,22,41,42]. This increased RR was associated with significant myelotoxicity, with Grade 3–4 neutropenia rates of 50–60% across all three studies. To the author’s knowledge, only one prospective phase II study of single-agent topoisomerase inhibitors in EP-PD-NEC has been published. In this study, 22 patients, over half of whom had a Ki-67 > 55%, were treated with a novel topoisomerase I inhibitor TLC388 at 40 mg/m2 [43]. Disappointingly, no responses were seen, and PFS was only 1.8 months, despite the improved in vitro data showing higher rates of topoisomerase I inhibition when compared to topotecan [44]. Single-agent topisomerase inhibitors do not, therefore, have a role currently in the management of patients with EP-PD-NEC.
Alkylating agents have also been assessed as monotherapy in the second-line setting in small prospective and retrospective studies that included patients with EP-PD-NEC. Kobayashi et al. conducted a randomised phase II trial in patients with EP-PD-NEC with temozolomide (200 mg/m2) given on days 1–5 of 28-day cycles. Responses were seen in 2 of 13 patients. Interestingly, both patients had higher proliferation rates (defined in the study as Ki-67 >50%) [45]. This confirms the findings of an earlier retrospective study, which also showed low response rates with monotherapy with temozolomide of 0% and a PFS of only 2.4 months in 16 patients with evaluable disease. Again, in this study, more than half of patients had a Ki-67 index ≥ 50%. The results of the second-line TENEC trial in the advanced setting are awaited to clarify the benefit of single-agent temozolomide in patients with EP-PD-NEC, and, in particular, the predictive value of the Ki-67 index (NCT04122911).
Given its efficacy in small cell lung cancer, Lurbinectedin, an inhibitor of oncogenic transcription, has been investigated as an option in NEN. A recent basket trial of second-line therapy including a heterogenous population of NENs, including NETs and NECs, showed PR in two out of thirty-two patients, one of which was a high-grade NEC. Without further information on subtypes, it is difficult to draw further conclusions about the efficacy of this therapy option in this setting [46].
The use of single-agent antimetabolite drugs in this setting has been explored less. S-1 is an antimetabolite cancer agent composed of tegafur 5-chloro-2, 4-dihydroxypyridine, and oteracil potassium. In 11 patients in the second-line advanced setting, it demonstrated an RR of 27%, with a PFS of only 2.8 months [22]. Given the relatively poor RR seen overall with monotherapies in EP-PD-NEC, doublet therapies have also been explored in the second-line setting.

3.3. Combination Chemotherapy Regimen in the Second-Line Setting

Given the comparable efficacy of first-line platinum/etoposide and platinum/irinotecan that can be seen in TOPIC-NEC, the use of irinotecan in doublets in the second-line setting in advanced EP-PD-NEC has been explored in several studies, and liposomal irinotecan has been examined in one prospective study. In a small retrospective study including 16 patients treated with irinotecan (180 mg/m2) and 5-fluorouracil (2000 mg/m2) in the second-line advanced setting, the RR was 33%, with a PFS of 4 months [47]. The BEVANEC phase II trial investigated the use of bevacizumab with chemotherapy in EP-PD-NEC and utilized FOLFIRI (Irinotecan 180 mg/m2, 5-FU, 2800 mg/m2) as its control arm with an ORR of 18% (11 of 61 patients). The majority of patients in this study had a Ki-67 index ≥ 55% (81%). Another prospective phase II study, NET-02, recruited 102 patients and randomised them 1:1 to liposomal–irinotecan (70 mg/m2) and 5-flourouracil (2400 mg/m2) IV every two weeks, or docetaxel IV every three weeks (75 mg/m2), until progressive disease or intolerance. Patients in this study were exclusively poorly differentiated and had grade 3 disease, with 90% having a Ki-67 index ≥ 55% and 91% being platinum resistant. In this clearly defined population, the ORR was 11.1% with liposomal irinotecan and 5-FU and 10.3% with single-agent docetaxel. Despite comparable RRs, the primary endpoint, the 6-month PFS rate, was nearly doubled in the combination arm (29.6% vs. 13.8% for liposomal irinotecan and 5FU vs. docetaxel). Importantly, grade 3 or 4 events were numerically less common in the doublet arm (51.7% vs. 55.2%). However, there was no difference in final OS between the arms, though the study was not powered to detect this [13].
The use of oxaliplatin in combination with 5-fluorouracil (5-FU) has also been explored in patients with advanced EP-PD-NEC. Hadoux et al. treated 20 patients with a two-weekly regimen of oxaliplatin (85 mg/m2) and 5-FU (2800 mg/m2) in the second-line advanced setting. Seventeen patients were evaluable, and responses were seen in 29%, including those who had not previously responded to first-line platinum therapy, with a median PFS of 4.6 months [48]. Further prospective trials may be warranted.
Given its efficacy in lower-grade NETs, particularly those of pancreatic origin and the relatively poor RR to single-agent temozolomide in EP-PD-NEC, temozolomide and capecitabine have also been investigated as a regimen. Thomas et al. performed a retrospective review of a diverse range of NETs treated with capecitabine and temozolomide. Of 26 patients treated in varying lines who had Ki-67 indices ≥ 20%, partial responses were seen in 12%. In the multivariable analysis, poor differentiation across all NENs was an adverse factor for response, but precise details on differentiation rates and RR were not given in this study [49]. In a study of patients with grade 3 NENs, including well-differentiated and poorly differentiated cases, an RR of 26% was seen amongst 46 patients with EP-PD-NECs in the second-line advanced setting [50]. Response rates in EP-PD-NEC were lower than those seen in well-differentiated cases (26% vs. 41%, respectively), and they were higher in EP-PD-NECs with Ki-67 < 55% vs. those ≥ 55%, in contrast to the pattern seen with first-line chemotherapy with etoposide and platinum [51]. The ongoing second-line phase II trial, SENECA, will prospectively compare temozolomide and capecitabine to 5-FU/irinotecan in second-line patients with EP-PD-NEC, and the comparison will be informative for future trial design. MGMT methylation has been suggested as a biomarker of response to temozolomide in neuroendocrine neoplasms. However, study results have varied, and limited evidence is available for NECs in particular; as such, currently, it cannot be recommended as a standard of care biomarker [45,52,53]. Pancreatic origin has also been shown to be predictive of better response to alkylating chemotherapy in lower-grade and well-differentiated NENs, and differences in MGMT promoter methylation may underly this. Nonetheless, the role of the organ of origin is less clear in poorly differentiated carcinomas [52,53].
In summary, the evidence base for second-line chemotherapy in patients with advanced EP-PD-NEC is limited (Table 1). Guidelines recommend regimens that have comparable efficacy in retrospective cohort studies and small phase 2 trials [18]. Given its limited toxicity and efficacy in a randomised phase 2 trial, 5-FU/irinotecan is an option for second-line treatment in patients with grade 3 EP-PD-NEC, particularly in those with Ki-67 indices above 55%. An option beyond that may be 5-FU/oxaliplatin, best supportive care, or clinical trials, if available.

4. Discussion

Improving on and Moving beyond Current Chemotherapy Regimens in Patients with EP-PD-NEC

Given the poor prognosis for patients with advanced EP-PD-NEC, it is clear that the treatment paradigm for these patients needs to improve. Though responses in the first-line advanced setting are common, rapid progression is the norm, and OS remains less than a year from the start of treatment [10]. The heterogeneity of this disease is striking, and recent developments and clarifications to classification confound the interpretation of many earlier trials and retrospective reviews. The predictive power of the Ki-67 index and morphology have become increasingly clear, and they are essential factors to be incorporated into inclusion criteria in future trial design [54]. Given the available evidence for differentiation and Ki-67 as predictive biomarkers of cytotoxic chemotherapy efficacy in patients with grade 3 NENs, it is essential that future trial outcomes are reported clearly for these relevant sub-groups.
In summary, however, the rate and duration of response to current cytotoxic regimens is poor, particularly in the second-line setting [11]. Furthermore, end-organ dysfunction can limit treatment options in relapsed disease, and consideration must be given to the safety and toxicity of regimen choices. In particular, liver dysfunction can limit the suitability of second-line irinotecan, and peripheral neuropathy may limit the use of an oxaliplatin-based regimen. Further studies of alternative systemic anti-cancer therapies alone or in combination with cytotoxic chemotherapy are warranted. Initial trials of angiogenesis inhibitors have disappointed, despite strong pre-clinical evidence. The BEVANEC phase 2 trial in EP-PD-NEC, predominantly with Ki-67 > 55% (85%), demonstrated that the addition of bevacizumab (5 mg/kg) to FOLFIRI did not improve the response rate (25.5% vs. 18.3%) or OS at 6 months (53% vs. 60%) [14].
The option for immunotherapy in patients with EP-PD-NEC has received much interest more recently. In small cell cancer of the lung, two phase 3 trials have shown an improvement in OS with the addition of Programmed cell death protein 1 (PD-1)/Programmed Cell Death Ligand 1 (PD-L1) directed therapy in combination with first-line chemotherapy [55,56]. A phase 3 trial is currently investigating the addition of atezolizumab to chemotherapy in the first-line advanced setting in patients with EP-PD-NEC (Table 2). Recent small phase II studies in patients with EP-PD-NEC suggest relatively limited RR to single-agent immunotherapy in the second-line setting [57,58,59]. Treatment with dual check point blockade (PD-1 and Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)) has demonstrated greater efficacy, with an ORR of 26–44% in patients with previously treated high-grade NENs [60,61]. Larger studies are awaited to validate this finding.
Clearly, novel therapies are required to improve outcomes in this disease, and a better understanding of its biology and, in particular, the somatic genetic drivers is urgently needed. Van Riet et al. completed one of the most comprehensive studies to date of high-grade extra-pulmonary neuroendocrine tumours, performing whole genome sequencing (WGS) of 85 cases, including NET and NEC (n = 15) samples [5]. They confirmed the striking difference in genomic profiles between G3 NETs and G3 NECs, with elevated point mutation rates and increased aneuploidy and chromosomal rearrangements in NEC cases. However, despite the comprehensive nature of WGS, only a fraction of cases harboured currently targetable genomic alterations, including small numbers of cases with tumour mutation burden (TMB) > 10 per MB and cases with KRAS and PIK3CA mutations. In NEC of colorectal origin, there appears to be a greater proportion of cases with targetable drivers, with a high prevalence of BRAFV600E mutations and microsatellite instability [16,62,63,64,65]. BRAF inhibitors in combination with MEK inhibitors have shown promise in isolated case reports of patients with EP-PD-NEC and BRAFV600E mutations [62,65]. Interestingly, unlike in colorectal adenocarcinomas, significant responses are seen without the need for combination with EGFR inhibition [63]. Whether BRAF inhibitors and/or immunotherapy will be more broadly successful in patients with EP-PD-NEC, as seen in colorectal cancer, awaits further large prospective clinical trials. Larger multi-omics studies incorporating NECs from a wide range of organs will be essential to identify new potential therapeutic avenues. Recent ENETs guidelines suggest comprehensive molecular profiling for NECs where available. Given the limited tumour agnostic approvals for many medications and the tissue specificity of actionable variants, e.g., BRAFV600E in colorectal NEC, the benefit of testing all NECs remains unproven. A limited gene-panel testing approach in tumours arising from specific sites is likely to provide similar benefits. A lack of suitable models for translational work has also hampered progress in the EP-PD-NEC field. Recently, it has been demonstrated that organoids can be established from EP-PD-NECs that recapitulate the genomic and transcriptomic findings seen in primary tissue [66]. The exploration of alternative strategies for model generation (for example, circulating tumour-cell-derived xenografts) is also required to ensure models are generated from chemotherapy-resistant cases, among other settings, as well as pre-treatment cases [4].
Given the rarity of EP-PD-NEC, large national and multinational collaborations and prospective trials are central to the understanding of its biology and in providing valuable insight into future therapeutic options. Given the paucity of identified targetable drivers, cytotoxic chemotherapy will likely continue to play a key role in future trials. Understanding the optimal regimens for each line of therapy is therefore crucial to future management and research into this tumour type.

5. Conclusions

The prospective data for the choice of chemotherapy regimen in patients with advanced EP-PD-NEC still lag behind those seen in many other cancer types. In large part, this has been due to the comparative rarity of this tumour and the heterogeneity of its biology. A better understanding of the biology of this disease has made it clear that simple biomarkers, including morphology (small cell versus large cell) and proliferation markers (Ki-67 <55% vs. >55%) have significant predictive power for determining the efficacy of chemotherapy. Future trials using appropriate stratification and large multi-national collaborations may help to clarify the most suitable chemotherapy regimens. Crucially, these trials may provide the ideal background for translational studies to identify the next generation of precision medicine approaches to potentially improve outcomes for patients with EP-PD-NEC.

Author Contributions

J.M.J.W. drafted the manuscript and addressed all co-author comments. All authors (R.A.H., J.W.V., J.M.J.W. and M.G.M.) reviewed and approved the final manuscript. M.G.M. advised regarding the concept and data for inclusion and reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

Jamie M.J. Weaver is funded by the NIHR as an academic clinical lecturer.

Acknowledgments

Jamie M. J. Weaver acknowledges the support of the NIHR, with whom he is funded as an academic clinical lecturer.

Conflicts of Interest

J.M.J.W. declares no conflict of interest. R.A.H. has served on the advisory board for Roche, BMS, Eisai, Celgene, Beigene, Ipsen, and BTG. He has received speaker fees from Eisai, Ipsen, Mylan, and PrimeOncology and has received travel and educational support from Bayer, BMS, and Roche; all are outside of the scope of this work. J.W.V.: Consulting or Advisory role for Agios, AstraZeneca, Delcath Systems, Keocyt, Genoscience Pharma, Incyte, Ipsen, Merck, Mundipharma EDO, Novartis, PCI Biotech, Pfizer, Pieris Pharmaceuticals, QED, and Wren Laboratories; Speakers’ Bureau for Imaging Equipment Limited, Ipsen, Novartis, and Nucana; and received Travel Grants from Celgene and Nucana; all are outside of the scope of this work. M.G.M. received research grant support from Servier, Ipsen, and NuCana. She has received travel and accommodation support from Bayer and Ipsen and speaker honoraria from Pfizer, Ipsen, NuCana, Mylan, and AAA. She has served on advisory boards for Celgene, Ipsen, Sirtex, Baxalta, Incyte, and Astra Zeneca; all are outside scope of this work.

References

  1. Nagtegaal, I.D.; Odze, R.D.; Klimstra, D.; Paradis, V.; Rugge, M.; Schirmacher, P.; Washington, K.M.; Carneiro, F.; Cree, I.A.; the WHO Classification of Tumours Editorial Board. The 2019 WHO classification of tumours of the digestive system. Histopathology 2020, 76, 182–188. [Google Scholar] [CrossRef] [PubMed]
  2. Dasari, A.; Mehta, K.; Byers, L.A.; Sorbye, H.; Yao, J.C. Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: A SEER database analysis of 162,983 cases. Cancer 2018, 124, 807–815. [Google Scholar] [CrossRef] [PubMed]
  3. Morizane, C.; Machida, N.; Honma, Y.; Okusaka, T.; Boku, N.; Kato, K.; Nomura, S.; Hiraoka, N.; Sekine, S.; Taniguchi, H.; et al. Effectiveness of Etoposide and Cisplatin vs Irinotecan and Cisplatin Therapy for Patients with Advanced Neuroendocrine Carcinoma of the Digestive System: The TOPIC-NEC Phase 3 Randomized Clinical Trial. JAMA Oncol. 2022, 8, 1447–1455. [Google Scholar] [CrossRef] [PubMed]
  4. Frizziero, M.; Kilgour, E.; Simpson, K.L.; Rothwell, D.G.; Moore, D.A.; Frese, K.K.; Galvin, M.; Lamarca, A.; Hubner, R.A.; Valle, J.W.; et al. Expanding Therapeutic Opportunities for Extrapulmonary Neuroendocrine Carcinoma. Clin. Cancer Res. 2022, 28, 1999–2019. [Google Scholar] [CrossRef] [PubMed]
  5. Van Riet, J.; van de Werken, H.J.G.; Cuppen, E.; Eskens, F.A.L.M.; Tesselaar, M.; van Veenendaal, L.M.; Klümpen, H.-J.; Dercksen, M.W.; Valk, G.D.; Lolkema, M.P.; et al. The genomic landscape of 85 advanced neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets. Nat. Commun. 2021, 12, 4612. [Google Scholar] [CrossRef] [PubMed]
  6. Hijioka, S.; Hosoda, W.; Matsuo, K.; Ueno, M.; Furukawa, M.; Yoshitomi, H.; Kobayashi, N.; Ikeda, M.; Ito, T.; Nakamori, S.; et al. Rb Loss and KRAS Mutation Are Predictors of the Response to Platinum-Based Chemotherapy in Pancreatic Neuroendocrine Neoplasm with Grade 3: A Japanese Multicenter Pancreatic NEN-G3 Study. Clin. Cancer Res. 2017, 23, 4625–4632. [Google Scholar] [CrossRef] [PubMed]
  7. Yachida, S.; Vakiani, E.; White, C.M.B.; Zhong, Y.; Saunders, T.H.; Morgan, R.; de Wilde, R.F.; Maitra, A.M.; Hicks, J.B.; DeMarzo, A.M.; et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am. J. Surg. Pathol. 2012, 36, 173–184. [Google Scholar] [CrossRef] [PubMed]
  8. Frizziero, M.; Durand, A.; Taboada, R.G.; Zaninotto, E.; Luchini, C.; Chakrabarty, B.; Hervieu, V.; Claro, L.C.; Zhou, C.; Cingarlini, S.; et al. Is the Morphological Subtype of Extra-Pulmonary Neuroendocrine Carcinoma Clinically Relevant? Cancers 2021, 13, 4152. [Google Scholar] [CrossRef] [PubMed]
  9. Vélayoudom-Céphise, F.L.; Duvillard, P.; Foucan, L.; Hadoux, J.; Chougnet, C.N.; Leboulleux, S.; Malka, D.; Guigay, J.; Goere, D.; Debaere, T.; et al. Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr. Relat. Cancer 2013, 20, 649–657. [Google Scholar] [CrossRef] [PubMed]
  10. Sorbye, H.; Welin, S.; Langer, S.W.; Vestermark, L.W.; Holt, N.; Osterlund, P.; Dueland, S.; Hofsli, E.; Guren, M.G.; Ohrling, K.; et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): The NORDIC NEC study. Ann. Oncol. 2013, 24, 152–160. [Google Scholar] [CrossRef]
  11. McNamara, M.G.; Frizziero, M.; Jacobs, T.; Lamarca, A.; Hubner, R.A.; Valle, J.W.; Amir, E. Second-line treatment in patients with advanced extra-pulmonary poorly differentiated neuroendocrine carcinoma: A systematic review and meta-analysis. Ther. Adv. Med. Oncol. 2020, 12, 1758835920915299. [Google Scholar] [CrossRef] [PubMed]
  12. Tanaka, H.; Hijioka, S.; Hosoda, W.; Ueno, M.; Kobayashi, N.; Ikeda, M.; Ito, T.; Kodama, Y.; Morizane, C.; Notohara, K.; et al. Pancreatic neuroendocrine carcinoma G3 may be heterogeneous and could be classified into two distinct groups. Pancreatology 2020, 20, 1421–1427. [Google Scholar] [CrossRef] [PubMed]
  13. McNamara, M.G.; Swain, J.; Craig, Z.; Sharma, R.; Faluyi, O.O.; Wadsley, J.; Morgan, C.; Wall, L.R.; Chau, I.; Reed, N.; et al. NET-02: A multicenter, randomized, phase II trial of liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients (pts) with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC). J. Clin. Oncol. 2022, 40, 4005. [Google Scholar]
  14. Walter, T.; Lievre, A.; Coriat, R.; Malka, D.; Elhajbi, F.; Di Fiore, F.; Hentic, O.; Smith, D.; Hautefeuille, V.; Roquin, G.; et al. Bevacizumab plus FOLFIRI after failure of platinum–etoposide first-line chemotherapy in patients with advanced neuroendocrine carcinoma (PRODIGE 41-BEVANEC): A randomised, multicentre, non-comparative, open-label, phase 2 trial. Lancet Oncol. 2023, 24, 297–306. [Google Scholar] [CrossRef]
  15. Kitagawa, Y.; Osumi, H.; Shinozaki, E.; Ota, Y.; Nakayama, I.; Suzuki, T.; Wakatsuki, T.; Ichimura, T.; Ogura, M.; Ooki, A.; et al. Safety and efficacy of amrubicin monotherapy in patients with platinum-refractory metastatic neuroendocrine carcinoma of the gastrointestinal tract: A single cancer center retrospective study. Cancer Manag. Res. 2019, 11, 5757–5764. [Google Scholar] [CrossRef]
  16. La Rosa, S.; Marando, A.; Furlan, D.; Sahnane, N.; Capella, C. Colorectal Poorly Differentiated Neuroendocrine Carcinomas and Mixed Adenoneuroendocrine Carcinomas: Insights into the Diagnostic Immunophenotype, Assessment of Methylation Profile, and Search for Prognostic Markers. Am. J. Surg. Pathol. 2012, 36, 601. [Google Scholar] [CrossRef] [PubMed]
  17. Rossi, A.; Di Maio, M.; Chiodini, P.; Rudd, R.M.; Okamoto, H.; Skarlos, D.V.; Früh, M.; Qian, W.; Tamura, T.; Samantas, E.; et al. Carboplatin- or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: The COCIS meta-analysis of individual patient data. J. Clin. Oncol. 2012, 30, 1692–1698. [Google Scholar] [CrossRef] [PubMed]
  18. Sorbye, H.; Grande, E.; Pavel, M.; Tesselaar, M.; Fazio, N.; Reed, N.S.; Knigge, U.; Christ, E.; Ambrosini, V.; Couvelard, A.; et al. European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for digestive neuroendocrine carcinoma. J. Neuroendocrinol. 2023, 35, e13249. [Google Scholar] [CrossRef] [PubMed]
  19. Moertel, C.G.; Kvols, L.K.; O’Connell, M.J.; Rubin, J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 1991, 68, 227–232. [Google Scholar] [CrossRef]
  20. Mitry, E.; Baudin, E.; Ducreux, M.; Sabourin, J.C.; Rufié, P.; Aparicio, T.; Lasser, P.; Elias, D.; Duvillard, P.; Schlumberger, M.; et al. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin. Br. J. Cancer 1999, 81, 1351–1355. [Google Scholar] [CrossRef]
  21. Frizziero, M.; Spada, F.; Lamarca, A.; Kordatou, Z.; Barriuso, J.; Nuttall, C.; McNamara, M.G.; Hubner, R.A.; Mansoor, W.; Manoharan, P.; et al. Carboplatin in Combination with Oral or Intravenous Etoposide for Extra-Pulmonary, Poorly-Differentiated Neuroendocrine Carcinomas. Neuroendocrinology 2019, 109, 100–112. [Google Scholar] [CrossRef] [PubMed]
  22. Yamaguchi, T.; Machida, N.; Morizane, C.; Kasuga, A.; Takahashi, H.; Sudo, K.; Nishina, T.; Tobimatsu, K.; Ishido, K.; Furuse, J.; et al. Multicenter retrospective analysis of systemic chemotherapy for advanced neuroendocrine carcinoma of the digestive system. Cancer Sci. 2014, 105, 1176–1181. [Google Scholar] [CrossRef] [PubMed]
  23. Pavel, M.; Öberg, K.; Falconi, M.; Krenning, E.P.; Sundin, A.; Perren, A.; Berruti, A. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2020, 31, 844–860. [Google Scholar] [CrossRef] [PubMed]
  24. Shah, M.H.; Goldner, W.S.; Benson, A.B.; Bergsland, E.; Blaszkowsky, L.S.; Brock, P.; Chan, J.; Das, S.; Dickson, P.V.; Fanta, P.; et al. Neuroendocrine and Adrenal Tumors, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw. 2021, 19, 839–868. [Google Scholar] [CrossRef]
  25. Lamarca, A.; Frizziero, M.; Barriuso, J.; McNamara, M.G.; Hubner, R.A.; Valle, J.W. Urgent need for consensus: International survey of clinical practice exploring use of platinum-etoposide chemotherapy for advanced extra-pulmonary high grade neuroendocrine carcinoma (EP-G3-NEC). Clin. Transl. Oncol. 2019, 21, 950–953. [Google Scholar] [CrossRef]
  26. Abdel-Rahman, O.; Koski, S.L. Cisplatin-Based versus Carboplatin-Based Chemotherapy for Extrapulmonary Neuroendocrine Carcinomas: A Real-World Study. Neuroendocrinology 2021, 112, 777–783. [Google Scholar] [CrossRef]
  27. Johnson, D.H.; Ruckdeschel, J.C.; Keller, J.H.; Lyman, G.H.; Kallas, G.J.; Macdonald, J.; Deconti, R.C.; Lee, J.; Ringenberg, Q.S.; Patterson, W.P.; et al. A randomized trial to compare intravenous and oral etoposide in combination with cisplatin for the treatment of small cell lung cancer. Cancer 1991, 67, 245–249. [Google Scholar] [CrossRef]
  28. Ali, A.S.; Grönberg, M.; Langer, S.W.; Ladekarl, M.; Hjortland, G.O.; Vestermark, L.W.; Österlund, P.; Welin, S.; Grønbæk, H.; Knigge, U.; et al. Intravenous versus oral etoposide: Efficacy and correlation to clinical outcome in patients with high-grade metastatic gastroenteropancreatic neuroendocrine neoplasms (WHO G3). Med. Oncol. 2018, 35, 47. [Google Scholar] [CrossRef]
  29. Liu, G.; Franssen, E.; Fitch, M.I.; Warner, E. Patient preferences for oral versus intravenous palliative chemotherapy. J. Clin. Oncol. 1997, 15, 110–115. [Google Scholar] [CrossRef] [PubMed]
  30. Veslemes, M.; Polyzos, A.; Latsi, P.; Dimitroulis, J.; Stamatiadis, D.; Dardoufas, C.; Rasidakis, A.; Katsilambros, N.; Jordanoglou, J. Optimal duration of chemotherapy in small cell lung cancer: A randomized study of 4 versus 6 cycles of cisplatin-etoposide. J. Chemother. 1998, 10, 136–140. [Google Scholar] [CrossRef]
  31. Sallam, M.; Wong, H.; Escriu, C. Treatment beyond four cycles of first line Platinum and Etoposide chemotherapy in real-life patients with stage IV Small Cell Lung Cancer: A retrospective study of the Merseyside and Cheshire Cancer network. BMC Pulm. Med. 2019, 19, 195. [Google Scholar] [CrossRef] [PubMed]
  32. Eads, J.R.; Catalano, P.J.; Fisher, G.A.; Rubin, D.; Iagaru, A.; Klimstra, D.S.; Konda, B.; Kwong, M.S.; Chan, J.A.; De Jesus-Acosta, A.; et al. Randomized phase II study of platinum and etoposide (EP) versus temozolomide and capecitabine (CAPTEM) in patients (pts) with advanced G3 non-small cell gastroenteropancreatic neuroendocrine neoplasms (GEPNENs): ECOG-ACRIN EA2142. J. Clin. Oncol. 2022, 40, 4020. [Google Scholar] [CrossRef]
  33. Butt, B.; Stokmo, H.; Ladekarl, M.; Tabaksblat, E.M.; Sorbye, H.; Revheim, M.; Hjortland, G. 1108P Folfirinox in the treatment of advanced gastroenteropancreatic neuroendocrine carsinomas. Ann. Oncol. 2021, 32, S915. [Google Scholar] [CrossRef]
  34. Hadoux, J.; Afchain, P.; Walter, T.; Tougeron, D.; Hautefeuille, V.; Monterymard, C.; Lorgis, V.; Thuillier, F.; Baudin, E.; Scoazec, J.Y.; et al. FOLFIRINEC: A randomized phase II trial of mFOLFIRINOX vs platinum-etoposide for metastatic neuroendocrine carcinoma of gastroenteropancreatic or unknown origin. Dig. Liver Dis. 2021, 53, 824–829. [Google Scholar] [CrossRef] [PubMed]
  35. Hainsworth, J.D.; Spigel, D.R.; Litchy, S.; Greco, F.A. Phase II trial of paclitaxel, carboplatin, and etoposide in advanced poorly differentiated neuroendocrine carcinoma: A Minnie Pearl Cancer Research Network Study. J. Clin. Oncol. 2006, 24, 3548–3554. [Google Scholar] [CrossRef] [PubMed]
  36. Baize, N.; Monnet, I.; Greillier, L.; Geier, M.; Lena, H.; Janicot, H.; Vergnenegre, A.; Crequit, J.; Lamy, R.; Auliac, J.-B.; et al. Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: An open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2020, 21, 1224–1233. [Google Scholar] [CrossRef]
  37. Hadoux, J.; Walter, T.; Kanaan, C.; Hescot, S.; Hautefeuille, V.; Perrier, M.; Tauveron, I.; Laboureau, S.; Cao, C.D.; Petorin, C.; et al. Second-line treatment and prognostic factors in neuroendocrine carcinoma: The RBNEC study. Endocr. Relat. Cancer 2022, 29, 569–580. [Google Scholar] [CrossRef] [PubMed]
  38. Apostolidis, L.; Bergmann, F.; Jäger, D.; Winkler, E.C. Efficacy of topotecan in pretreated metastatic poorly differentiated extrapulmonary neuroendocrine carcinoma. Cancer Med. 2016, 5, 2261–2267. [Google Scholar] [CrossRef] [PubMed]
  39. Olsen, I.H.; Knigge, U.; Federspiel, B.; Hansen, C.P.; Skov, A.; Kjær, A.; Langer, S.W. Topotecan monotherapy in heavily pretreated patients with progressive advanced stage neuroendocrine carcinomas. J. Cancer 2014, 5, 628–632. [Google Scholar] [CrossRef]
  40. O’Brien, M.E.; Ciuleanu, T.-E.; Tsekov, H.; Shparyk, Y.; Čučeviá, B.; Juhasz, G.; Thatcher, N.; Ross, G.A.; Dane, G.C.; Crofts, T. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J. Clin. Oncol. 2006, 24, 5441–5447. [Google Scholar] [CrossRef]
  41. Araki, T.; Takashima, A.; Hamaguchi, T.; Honma, Y.; Iwasa, S.; Okita, N.; Kato, K.; Yamada, Y.; Hashimoto, H.; Taniguchi, H.; et al. Amrubicin in patients with platinum-refractory metastatic neuroendocrine carcinoma and mixed adenoneuroendocrine carcinoma of the gastrointestinal tract. Anticancer Drugs 2016, 27, 794–799. [Google Scholar] [CrossRef] [PubMed]
  42. Ebata, T.; Shimoi, T.; Ishiwata, T.; Iwasawa, S.; Bun, S.; Yunokawa, M.; Yonemori, K.; Takiguchi, Y.; Tamura, K. Amrubicin Monotherapy for Patients with Platinum-Pretreated Non-Gastrointestinal Non-Pancreatic Extrapulmonary Neuroendocrine Carcinoma. Oncology 2017, 93, 177–182. [Google Scholar] [CrossRef]
  43. Chen, M.H.; Chou, W.C.; Hsiao, C.F.; Jiang, S.S.; Tsai, H.J.; Liu, Y.C.; Hsu, C.; Shan, Y.S.; Hung, Y.P.; Hsich, C.H.; et al. An Open-Label, Single-Arm, Two-Stage, Multicenter, Phase II Study to Evaluate the Efficacy of TLC388 and Genomic Analysis for Poorly Differentiated Neuroendocrine Carcinomas. Oncologist 2020, 25, e782–e788. [Google Scholar] [CrossRef] [PubMed]
  44. Huang, G.; Wang, H.; Yang, L.-X. Enhancement of radiation-induced DNA damage and inhibition of its repair by a novel camptothecin analog. Anticancer Res. 2010, 30, 937–944. [Google Scholar] [PubMed]
  45. Kobayashi, N.; Takeda, Y.; Okubo, N.; Suzuki, A.; Tokuhisa, M.; Hiroshima, Y.; Ichikawa, Y. Phase II study of temozolomide monotherapy in patients with extrapulmonary neuroendocrine carcinoma. Cancer Sci. 2021, 112, 1936–1942. [Google Scholar] [CrossRef] [PubMed]
  46. Longo-Muñoz, F.; Castellano, D.; Alexandre, J.; Chawla, S.P.; Fernández, C.; Kahatt, C.; Alfaro, V.; Siguero, M.; Zeaiter, A.; Moreno, V.; et al. Lurbinectedin in patients with pretreated neuroendocrine tumours: Results from a phase II basket study. Eur. J. Cancer 2022, 172, 340–348. [Google Scholar] [CrossRef] [PubMed]
  47. Hentic, O.; Hammel, P.; Couvelard, A.; Rebours, V.; Zappa, M.; Palazzo, M.; Maire, F.; Goujon, G.; Gillet, A.; Lévy, P.; et al. FOLFIRI regimen: An effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3. Endocr. Relat. Cancer 2012, 19, 751–757. [Google Scholar] [CrossRef] [PubMed]
  48. Hadoux, J.; Malka, D.; Planchard, D.; Scoazec, J.Y.; Caramella, C.; Guigay, J.; Boige, V.; Leboulleux, S.; Burtin, P.; Berdelou, A.; et al. Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma. Endocr. Relat. Cancer 2015, 22, 289–298. [Google Scholar] [CrossRef]
  49. Thomas, K.; Voros, B.A.; Meadows-Taylor, M.; Smeltzer, M.P.; Griffin, R.; Boudreaux, J.P.; Thiagarajan, R.; Woltering, E.A.; Ramirez, R.A. Outcomes of Capecitabine and Temozolomide (CAPTEM) in Advanced Neuroendocrine Neoplasms (NENs). Cancers 2020, 12, 206. [Google Scholar] [CrossRef]
  50. Chan, D.L.; Bergsland, E.K.; Chan, J.A.; Gadgil, R.; Halfdanarson, T.R.; Hornbacker, K.; Kelly, V.; Kunz, P.L.; McGarrah, P.W.; Raj, N.P.; et al. Temozolomide in Grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: A Multicenter Retrospective Review. Oncologist 2021, 26, 950–955. [Google Scholar] [CrossRef]
  51. Elvebakken, H.; Perren, A.; Scoazec, J.Y.; Tang, L.H.; Federspiel, B.; Klimstra, D.S.; Vestermark, L.W.; Ali, A.S.; Zlobec, I.; Myklebust, T.Å.; et al. A Consensus-Developed Morphological Re-Evaluation of 196 High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms and Its Clinical Correlations. Neuroendocrinology 2021, 111, 883–894. [Google Scholar] [CrossRef] [PubMed]
  52. De Mestier, L.; Couvelard, A.; Blazevic, A.; Hentic, O.; de Herder, W.W.; Rebours, V.; Paradis, V.; Ruszniewski, P.; Hofland, L.J.; Cros, J. Critical appraisal of MGMT in digestive NET treated with alkylating agents. Endocr. Relat. Cancer 2020, 27, R391–R405. [Google Scholar] [CrossRef]
  53. Welin, S.; Sorbye, H.; Sebjornsen, S.; Knappskog, S.; Busch, C.; Öberg, K. Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy. Cancer 2011, 117, 4617–4622. [Google Scholar] [CrossRef] [PubMed]
  54. Lamarca, A.; Walter, T.; Pavel, M.; Borbath, I.; Freis, P.; Nuñez, B.; Childs, A.; McNamara, M.G.; Hubner, R.A.; Garcia-Carbonero, R.; et al. Design and Validation of the GI-NEC Score to Prognosticate Overall Survival in Patients with High-Grade Gastrointestinal Neuroendocrine Carcinomas. J. Natl. Cancer Inst. 2017, 109, djw277. [Google Scholar] [CrossRef] [PubMed]
  55. Horn, L.; Mansfield, A.S.; Szczęsna, A.; Havel, L.; Krzakowski, M.; Hochmair, M.J.; Huemer, F.; Losonczy, G.; Johnson, M.L.; Nishio, M.; et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N. Engl. J. Med. 2018, 379, 2220–2229. [Google Scholar] [CrossRef] [PubMed]
  56. Paz-Ares, L.; Dvorkin, M.; Chen, Y.; Reinmuth, N.; Hotta, K.; Trukhin, D.; Statsenko, G.; Hochmair, M.J.; Özgüroğlu, M.; Ji, J.H.; et al. Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): A randomised, controlled, open-label, phase 3 trial. Lancet 2019, 394, 1929–1939. [Google Scholar] [CrossRef]
  57. Raj, N.; Chan, J.A.; Wang, S.J.; Aggarwal, R.R.; Calabrese, S.; DeMore, A.; Fong, L.; Grabowsky, J.; Hope, T.A.; Kolli, K.P.; et al. Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas. Br. J. Cancer 2023, 129, 291–300. [Google Scholar] [CrossRef]
  58. Vijayvergia, N.; Dasari, A.; Deng, M.; Litwin, S.; Al-Toubah, T.; Alpaugh, R.K.; Dotan, E.; Hall, M.J.; Ross, N.M.; Runyen, M.M.; et al. Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: Joint analysis of two prospective, non-randomised trials. Br. J. Cancer 2020, 122, 1309–1314. [Google Scholar] [CrossRef] [PubMed]
  59. Yao, J.C.; Strosberg, J.; Fazio, N.; Pavel, M.E.; Bergsland, E.; Ruszniewski, P.; Halperin, D.M.; Li, D.; Tafuto, S.; Raj, N.; et al. Spartalizumab in metastatic, well/poorly differentiated neuroendocrine neoplasms. Endocr. Relat. Cancer 2021, 28, 161–172. [Google Scholar] [CrossRef]
  60. Patel, S.P.; Mayerson, E.; Chae, Y.K.; Strosberg, J.; Wang, J.; Konda, B.; Hayward, J.; McLeod, C.M.; Chen, H.X.; Sharon, E.; et al. A phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609: High-grade neuroendocrine neoplasm cohort. Cancer 2021, 127, 3194–3201. [Google Scholar] [CrossRef]
  61. Patel, S.P.; Othus, M.; Chae, Y.K.; Giles, F.J.; Hansel, D.E.; Singh, P.P.; Fontaine, A.; Shah, M.H.; Kasi, A.; Baghdadi, T.A.; et al. A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic Neuroendocrine Tumors. Clin. Cancer Res. 2020, 26, 2290–2296. [Google Scholar] [CrossRef]
  62. Burkart, J.; Owen, D.; Shah, M.H.; Abdel-Misih, S.R.; Roychowdhury, S.; Wesolowski, R.; Haraldsdottir, S.; Reeser, J.W.; Samorodnitsky, E.; Smith, A.; et al. Targeting BRAF Mutations in High-Grade Neuroendocrine Carcinoma of the Colon. J. Natl. Compr. Canc. Netw. 2018, 16, 1035–1040. [Google Scholar] [CrossRef] [PubMed]
  63. Capdevila, J.; Arqués, O.; Hernández Mora, J.R.; Matito, J.; Caratù, G.; Mancuso, F.M.; Landolfi, S.; Barriuso, J.; Jimenez-Fonseca, P.; Lopez Lopez, C.; et al. Epigenetic EGFR Gene Repression Confers Sensitivity to Therapeutic BRAFV600E Blockade in Colon Neuroendocrine Carcinomas. Clin. Cancer Res. 2020, 26, 902–909. [Google Scholar] [CrossRef]
  64. Dizdar, L.; Werner, T.A.; Drusenheimer, J.C.; Möhlendick, B.; Raba, K.; Boeck, I.; Anlauf, M.; Schott, M.; Göring, W.; Esposito, I.; et al. BRAFV600E mutation: A promising target in colorectal neuroendocrine carcinoma. Int. J. Cancer 2019, 144, 1379–1390. [Google Scholar] [CrossRef] [PubMed]
  65. Klempner, S.J.; Gershenhorn, B.; Tran, P.; Lee, T.K.; Erlander, M.G.; Gowen, K.; Schrock, A.B.; Morosini, D.; Ross, J.S.; Miller, V.A.; et al. BRAFV600E Mutations in High-Grade Colorectal Neuroendocrine Tumors May Predict Responsiveness to BRAF-MEK Combination Therapy. Cancer Discov. 2016, 6, 594–600. [Google Scholar] [CrossRef] [PubMed]
  66. Kawasaki, K.; Toshimitsu, K.; Matano, M.; Fujita, M.; Fujii, M.; Togasaki, K.; Ebisudani, T.; Shimokawa, M.; Takano, A.; Takahashi, S.; et al. An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping. Cell 2020, 183, 1420–1435.e21. [Google Scholar] [CrossRef]
Table 1. Some selected ongoing chemotherapy trials in patients with EP-PD-NEC.
Table 1. Some selected ongoing chemotherapy trials in patients with EP-PD-NEC.
Clinicaltrials.gov
Trial Identifier		Trial RegimenLine of TreatmentPhaseRecruitment TargetPrimary Endpoint
NCT02595424TEMCAP vs. EPFirst II59PFS
NCT05058651Atezolizumab + EP vs. EPFirstII/III189OS
NCT04325425mFolFIrinOx vs. EPFirstII218PFS
NCT04042714TAS-102SecondII14ORR
NCT03387592FolFIri vs. TEMCAPSecondII112DCR/AE incidence
TEMCAP, temozolomide and capecitabine; FolFIri, 5-flurouracil and irinotecan; TAS-102, trifluridine and tipiracil hydrochloride; mFolFIrinOx, modified 5-Flurouracil, irinotecan, and oxalplatin; EP, cisplatin or carboplatin and etoposide; DCR, disease control rate; OS, overall survival; PFS, progression-free survival; AE, adverse event.
Table 2. Published randomised control trials in first- and second-line treatment of EP-PD-NEC.
Table 2. Published randomised control trials in first- and second-line treatment of EP-PD-NEC.
Trial IDTrial RegimenLine of TreatmentPhaseRecruitment NumbersMain Primary SitesKi-67 ≥ 55%ORRPFS (Months)OS
TOPIC-NECEP vs. IP1III170Upper GI82% vs. 81%54% vs. 52%5.6 vs. 5.112.5 vs. 10.9 months
BevanecFOLFIRI + Bev vs. FOLFIRI2II150Colorectal86% vs. 76%25% vs. 18%3.7 vs. 3.56 months, 53% vs. 61%
NET-02Nal-IRI/5FU vs. Docetaxel2II59Upper GI90% vs. 90%11% vs. 10%3 vs. 26 months, 29.6% vs. 13.8%
EP, cisplatin or carboplatin and etoposide; IP, cisplatin or carboplatin and irinotecan; FOLFIRI, 5-flurouracil and irinotecan; Bev, Bevacizumab; Nal-IRI/5FU, Nano-liposomal irinotecan and 5-flurouracil; GI, gastrointestinal; ORR, overall response rate; PFS, progression-free survival; OS, overall survival. Note: Ki-67 values for TOPIC-NEC were reported as those patients above 50%, not 55%. OS for BEVANEC and NET-O2 is given as 6-month OS percentage. No significant difference was seen for the comparison of OS, ORR, and PFS in TOPIC-NEC; Bevanec and NET-02 were non-comparative phase 2 studies, so no comparisons were made directly between arms for ORR, PFS and OS.
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Weaver, J.M.J.; Hubner, R.A.; Valle, J.W.; McNamara, M.G. Selection of Chemotherapy in Advanced Poorly Differentiated Extra-Pulmonary Neuroendocrine Carcinoma. Cancers 2023, 15, 4951. https://doi.org/10.3390/cancers15204951

AMA Style

Weaver JMJ, Hubner RA, Valle JW, McNamara MG. Selection of Chemotherapy in Advanced Poorly Differentiated Extra-Pulmonary Neuroendocrine Carcinoma. Cancers. 2023; 15(20):4951. https://doi.org/10.3390/cancers15204951

Chicago/Turabian Style

Weaver, Jamie M. J., Richard A. Hubner, Juan W. Valle, and Mairead G. McNamara. 2023. "Selection of Chemotherapy in Advanced Poorly Differentiated Extra-Pulmonary Neuroendocrine Carcinoma" Cancers 15, no. 20: 4951. https://doi.org/10.3390/cancers15204951

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