Version July 2025
INTRODUCTION —
Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies characterized by variable biologic behavior. The clinical behavior and prognosis of these tumors correlate closely with histologic differentiation and grade (table 1). NENs can also arise from many different sites since neuroendocrine cells are distributed throughout the body. (See "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms".)
The clinical presentation, diagnosis, and management of poorly differentiated gastroenteropancreatic (GEP) neuroendocrine carcinoma (NEC) is presented here. Large and small cell carcinoma involving the lung and small cell carcinoma involving the bladder, cervix, and other sites are discussed separately. (See "Large cell neuroendocrine carcinoma of the lung" and "Extensive-stage small cell lung cancer: Initial management" and "Small cell carcinoma of the bladder" and "Small cell neuroendocrine carcinoma of the cervix" and "Extrapulmonary small cell cancer".)
Other related topics on GEP NENs are also presented separately.
●(See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)
●(See "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors".)
DEFINITION —
Poorly differentiated gastroenteropancreatic (GEP) neuroendocrine carcinomas (NEC) are defined as neuroendocrine neoplasms (NENs) arising from the gastrointestinal (GI) tract or pancreas that exhibit poor histologic differentiation (table 1). These tumors are not assigned a formal tumor grade because they are always high-grade (grade 3). In this topic, poorly differentiated gastroenteropancreatic neuroendocrine carcinoma will be called "GEP NEC." (See "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms", section on 'Poorly differentiated NEC'.)
EPIDEMIOLOGY
●Incidence – GEP NEC is very rare [1-6]. In a cohort study from the Netherlands Cancer Registry between 2000 to 2010, the annual incidence of GEP NEC was 0.54 per 100,000 inhabitants [1]. Large cell GEP NEC was twice as common as small cell GEP NEC (incidence of 0.36 versus 0.18 per 100,000 inhabitants). Similarly, in an observational study from the Surveillance, Epidemiology, and End Results (SEER) database in the United States, the incidence of colorectal NEC was estimated at 0.2 per 100,000 inhabitants [2].
●Sex – The incidence is similar between males and females. However, males are more likely to present with a GEP NEC at certain sites, such as the esophagus or the stomach [7-9].
RISK FACTORS —
The risk factors for GEP NEC are not well established. Smoking is a risk factor, although the association is not as strong as that seen with lung cancer [1,10,11]. Risk factors for esophageal NEC include a prior history of achalasia, gastroesophageal reflux disease, alcohol use, or Barrett metaplasia. Risk for colorectal NEC includes colonic adenomas and ulcerative colitis [10,12].
A well-differentiated GEP neuroendocrine tumor (NET) is generally not a risk factor for developing a GEP NEC. NEC generally does not arise from well-differentiated NET because these two entities are almost never found together on histopathology [10,13]. It is highly uncommon for an established well-differentiated NET to transform into an NEC, despite the ability of some well-differentiated NET to exhibit high tumor grade and proliferation rates [14]. However, transformation of a grade 1 or grade 2 NET to an NEC following peptide receptor radionuclide therapy (PRRT) has been reported [15]. (See "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms", section on 'Well-differentiated high-grade (G3) NET'.)
In contrast to NET, NEC is not associated with a hereditary condition. Germline pathogenic or highly likely pathogenic variants have been found in 4.5 percent of patients with NEC [16].
CLINICAL PRESENTATION —
The clinical presentation of GEP NEC is variable and depends upon the site of the primary tumor and extent of disease.
Primary tumor site — Although the incidence is variable, colorectal primary tumors account for most GEP NEC (approximately 41 percent), followed by upper gastrointestinal (GI; 23 percent) and pancreatic (20 percent) primary tumors [10,17-22]. Small bowel primary tumors are rare. Small cell NEC is more commonly seen in tumors with esophageal, gallbladder, and anal primary sites.
Most primary NEC within the large bowel are located distally. In one observational study, the most common site of origin was the rectum (38 percent), followed by the cecum (27 percent), sigmoid colon (17 percent), transverse colon (12 percent), and ascending colon (6 percent) [12].
Clinical symptoms
Symptoms of metastatic disease — Most patients with NEC present with metastatic disease (50 percent or more) [23] due to the aggressive nature of this cancer [24-26]. Common sites of metastases include liver, bone, and lungs. Symptoms related to distant metastases may include abdominal pain from liver metastases, bone pain due to skeletal metastases, and respiratory complaints due to pulmonary metastases. Rarely, patients may present with neurologic symptoms from brain metastases; however, the risk of brain metastases is much lower than small cell lung cancer (SCLC) [27-29].
Symptoms from the local tumors — Patients with locoregional disease may present with symptoms that are like those seen with other types of tumors arising in the same site. As examples:
●Esophageal primary – Progressive dysphagia and indigestion are common complaints. Other symptoms may include weight loss and cachexia due to anorexia and decreased caloric intake [30,31]. (See "Clinical manifestations, diagnosis, and staging of esophageal cancer", section on 'Clinical manifestations'.)
●Large bowel primary tumor – Possible signs and symptoms of a large bowel NEC include abdominal pain, hematochezia, large bowel obstruction, changes in bowel habits, and iron deficiency anemia. Such symptoms are like those seen with colorectal adenocarcinoma. (See "Clinical presentation, diagnosis, and staging of colorectal cancer", section on 'Symptoms from the local tumor'.)
Nearly all GEP NEC are nonfunctional (ie, not hormone-secreting) due to the poorly differentiated state of the tumor [25,26,32,33]. (See "Clinical features of carcinoid syndrome".)
DIAGNOSTIC EVALUATION
How is the tumor identified? — In general, tumors due to GEP NEC are initially identified clinically on diagnostic studies obtained to assess disease-related symptoms. These include imaging studies (eg, computed tomography [CT] or magnetic resonance imaging [MRI] of the abdomen and pelvis) or endoscopic evaluation (eg, colonoscopy, upper endoscopy).
Tissue specimen (diagnosis) — The diagnosis of a GEP NEC is typically confirmed based on histopathologic evaluation of tumor tissue, either from a biopsy or surgically-excised specimen. These tumors are classified by their morphologic appearance, distinct immunohistochemistry patterns, tumor differentiation (ie, resemblance of the tumor histology to normal neuroendocrine tissue), and tumor grade (ie, tumor proliferative activity measured by mitotic rate or Ki-67 proliferative index (table 1)). A summary is provided below, with full details on the pathology and classification of GEP NEC discussed separately. (See "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms", section on 'Histopathology and immunohistochemistry'.)
●Histologic classification – GEP NEC are classified as either small cell type NEC or large cell type NEC (figure 1). Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) typically have components of a poorly differentiated NEC. (See 'Mixed neuroendocrine-non-neuroendocrine neoplasms' below.)
●Tumor grade and differentiation – Distinguishing a well-differentiated grade 3 NET (NET G3) from an NEC can be challenging (table 1) [34]. Both NEC and NET G3 are high-grade (grade 3) tumors, either with a high mitotic rate (greater than 20 per 2 mm2) and/or high Ki-67 proliferative index (greater than 20 percent). Although a Ki-67 proliferative rate between 20 to 55 percent can be seen with either a NET G3 or NEC, a higher Ki-67 proliferative index (greater than 55 percent) usually indicates a NEC (figure 2). A mitotic rate greater than 20 per 10 high-powered fields also usually indicates an NEC, since most NET G3 fall into the grade 3 range solely based on a Ki-67 index between 20 and 55 percent.
Therefore, tumors classified as an NEC with a Ki-67 less than 55 percent should re-evaluated by a pathologist for the possibility that the tumor is a NET G3. Likewise, tumors that are classified as a NET G3 but have a Ki-67 index greater than 55 percent should be re-evaluated for the possibility that the tumor is an NEC. Further details on assessing tumor grade and stage in neuroendocrine neoplasms (NENs) are discussed separately. (See "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms", section on 'How to distinguish between NET G3 and NEC' and "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms", section on 'Assessing tumor grade'.)
Imaging studies — For patients with a histologically confirmed diagnosis of GEP NEC, imaging studies should be performed as part of the staging evaluation. All patients with GEP NEC should undergo a contrast-enhanced CT of the chest, abdomen, and pelvis to assess the extent of disease. In contrast to well-differentiated NETs, multiphase CT imaging is generally not required to stage GEP NEC. For patients who are being evaluated for surgery, we also obtain a fluorodeoxyglucose-positron emission tomography (FDG-PET)-CT to exclude metastatic disease prior to resection. FDG-PET-CT is helpful because it demonstrates positive uptake in nearly all NEC (92 percent or more) [26].
We do not routinely obtain central nervous system (CNS) imaging in patients lacking neurologic symptoms because GEP NEC is associated with a lower incidence of brain metastases than small cell lung cancer (SCLC) [27-29].
For patients with GEP NEC, we also do not routinely obtain somatostatin receptor (SSTR)-based imaging, such as gallium Ga-68 dotatate PET-CT. Most GEP NEC are poorly differentiated and thus do not express SSTRs. As a result, SSTR-based imaging is negative in over one-half of GEP NEC [26,35-37].
Somatic tumor tissue testing — Patients with advanced or metastatic disease should be tested for actionable mutations that may impact available treatment options. Such testing is typically performed using next-generation sequencing (NGS) on a tissue sample obtained either from the primary tumor or a metastatic site. For patients with inadequate or unavailable tissue samples, actionable mutations can alternatively be identified through cell-free deoxyribonucleic acid (DNA) testing (ie, NGS testing on blood samples) [38]. Ideally, somatic tumor tissue testing should be performed early in the disease course so that results are available at the time of progression.
Examples of targetable mutations that are seen in GEP NEC include mismatch repair deficiency (dMMR)/high microsatellite instability (MSI-H; 5 percent) and BRAF V600E mutations (50 percent of colorectal NEC) [39]. Other mutations include high tumor mutational burden (TMB-H) and, less commonly, NTRK and RET gene fusions. (See 'Actionable molecular alterations' below.)
Tumor markers — We do not routinely obtain chromogranin-A as part of the postdiagnostic evaluation of a GEP NEC, which is variably secreted by these tumors [19,26,35]. Imaging studies generally demonstrate treatment responses quite clearly in this disease, which are not always paralleled by changes in chromogranin-A even if it is elevated at diagnosis. We also do not routinely measure serum or urine levels of the serotonin metabolite 5-hydroxyindoleacetic acid, as these tumors are poorly differentiated and rarely secrete serotonin. (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors".)
STAGING SYSTEM —
Several staging systems are available for poorly differentiated NEC.
AJCC staging system — Poorly differentiated GEP NEC are staged using the same American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system that is used for adenocarcinomas at the individual primary tumor sites such as the esophagus (table 2), stomach (table 3), pancreas (table 4), gallbladder (table 5), small bowel (table 6), colon or rectum (table 7), and anal canal (table 8).
ENETS staging system — The European Neuroendocrine Tumor Society (ENETS) has proposed a staging system that is similar to the AJCC staging system [40,41].
TREATMENT OF LOCOREGIONAL DISEASE —
Few patients with GEP NEC will present with localized or locoregional disease and no distant metastases (stage I to III disease) [26,37]. As such, treatment strategies are mainly based on limited observational studies from heterogeneous populations of extrapulmonary NEC that included GEP NEC [28,42-45] or extrapolated from the management of small cell lung cancer (SCLC). Locoregional GEP NEC is typically treated with curative intent using combinations of surgery, chemotherapy, and/or radiation therapy (RT). Treatment is often individualized, and multidisciplinary evaluation is necessary, with input from surgical oncology, medical oncology, and radiation oncology. Our management approach is generally consistent with treatment guidelines from the National Comprehensive Cancer Network (NCCN) [46], the North American Neuroendocrine Tumor Society (NANETS) [47,48], and the European Neuroendocrine Tumor Society (ENETS) [49,50].
Unfortunately, despite aggressive multimodality therapy, many patients with locoregional disease eventually relapse and develop metastatic disease. As data are limited for the optimal treatment approach, clinical trial enrollment is encouraged, where available.
Non-esophageal NEC — The management of localized or locoregionally advanced non-esophageal GEP NEC is as follows. In all cases, the preferred chemotherapy regimen is platinum plus etoposide, and the addition of concurrent RT to chemotherapy is an individualized decision. (See 'Neoadjuvant chemotherapy' below and 'When is chemoradiation used?' below.)
•Localized resectable disease – For patients with a non-esophageal primary GEP NEC (eg, colorectal, gastric, gallbladder, pancreatic) that are localized (T1 to T2N0) and resectable, we suggest surgical resection plus adjuvant chemotherapy rather than surgery alone. Neoadjuvant chemotherapy followed by surgery is also an appropriate alternative, especially for patients with a high-estimated risk of postoperative morbidity where adjuvant treatment may be delayed [47].
•Locoregionally advanced, resectable disease – For patients with locoregionally advanced (T3 to T4 and/or lymph node-positive) resectable disease, we suggest neoadjuvant chemotherapy (with or without concurrent RT) followed by surgery rather than surgery alone, given the aggressive nature of poorly differentiated NEC. For patients with tumor sites that are resectable but at high risk for surgical morbidity (eg, distal rectum, pancreatic head), definitive chemoradiation (CRT) is an option [51], but surgery is likely still needed to achieve appropriate overall survival (OS) outcomes (five-year OS of 22 percent for stage III rectal NEC and five-year OS of 27 percent for stage III pancreatic NEC) [17]. (See 'When is chemoradiation used?' below.)
•Unresectable disease – For patients with unresectable locoregional disease, we suggest the combination of chemotherapy and RT (administered either concurrently or sequentially) rather than either modality alone. (See 'When is chemoradiation used?' below.)
Systemic therapy used to treat metastatic disease, however, is also an appropriate alternative. (See 'Initial treatment of metastatic disease' below.)
Neoadjuvant chemotherapy — For all patients with a localized or locoregional GEP NEC (regardless of the primary tumor site), we offer chemotherapy with platinum (either cisplatin or carboplatin) plus etoposide. In most cases, chemotherapy is administered in the neoadjuvant setting prior to surgery. Due to the aggressive nature of these GEP NEC, neoadjuvant chemotherapy offers the opportunity to treat possible early micrometastatic disease and to reduce tumor burden prior to surgery [50]. Observational studies of locoregionally advanced GEP NEC also suggest that neoadjuvant chemotherapy, in most cases with platinum plus etoposide, is associated with improved OS [52-54].
However, adjuvant chemotherapy may be appropriate in other cases, such as localized GEP NEC that is incidentally diagnosed only after initial surgical resection. (See 'Adjuvant chemotherapy' below.)
In select situations, chemotherapy and RT may be administered together. (See 'When is chemoradiation used?' below.)
Surgery — In patients with non-esophageal localized GEP NEC who are receiving multimodality therapy, data for the benefits of surgical resection come from retrospective studies, which suggest that potentially curative surgery is an independent prognostic factor for OS [17,55-65]. We also suggest adjuvant systemic therapy after radical surgery. (See 'Adjuvant chemotherapy' below.)
As an example, an observational study from the National Cancer Database between 2004 and 2016 included 2314 patients with stage I to III digestive tract NEC [51]. For the entire study population, the median OS was 21 months, and five-year OS was 29 percent. Colon NEC was associated with the longest OS (median 29 months; five-year OS 40 percent), while gallbladder and biliary NEC were associated with the shortest OS (median 15 months; five-year OS 21 percent). Small cell morphology was associated with worse OS compared with large cells and other histologies (median 18 versus 22 months). Even in patients undergoing CRT, surgery was the only prognostic variable that significantly affected OS in stages I to II disease (hazard ratio [HR] 0.63, 95% CI 0.44-0.91), and there was also a nonstatistically significant trend towards better OS with stage III disease (HR 0.77, 95% CI 0.59-1.01). However, patients requiring surgery at sites with higher surgical morbidity were less likely to undergo surgical resection and were treated with CRT instead.
For colorectal primary tumors, the benefit of surgery may depend on the histologic subtype (small cell versus non-small cell). In an observational study of 502 patients with stage I to III colorectal NEC, surgery was associated with improved OS relative to no surgery (three-year OS 40 versus 18 percent) [55] Among patients with localized non-small cell colorectal cancer NEC, surgery was associated with improved OS relative to no surgery (median OS 21 versus 6 months), whereas among those with small cell colorectal cancer NEC, surgery was not associated with an OS benefit (median survival 18 versus 14 months).
Adjuvant chemotherapy — For patients with localized GEP NEC who are treated with resection, we suggest adjuvant chemotherapy with four to six cycles of platinum (either cisplatin or carboplatin) plus etoposide. Both regimens are acceptable and likely equally effective, and selection is based on toxicity profiles of cisplatin and carboplatin [66]. This approach is extrapolated from the treatment paradigm for limited-stage SCLC, which is discussed separately. (See "Limited-stage small cell lung cancer: Initial management", section on 'Overview of treatment and benefits'.)
The use of adjuvant chemotherapy in localized, resected GEP NEC is based on retrospective studies, which are difficult to interpret due to selection bias. Furthermore, observational studies demonstrate conflicting results and suggest that the benefit of adjuvant therapy might depend, in part, on the primary tumor site. In some studies, adjuvant chemotherapy was associated with an OS benefit for colorectal NEC [67-70], whereas other studies did not find an OS benefit for other primary sites such as the stomach (both NEC and mixed neuroendocrine-non-neuroendocrine neoplasms [MiNEN]), pancreas, and small bowel [62,71,72].
Esophageal NEC — For patients with a localized or locoregionally advanced esophageal primary NEC (regardless of resectability), we suggest RT plus chemotherapy rather than surgery plus chemotherapy. Chemotherapy and RT can be administered either concurrently or sequentially, and the preferred chemotherapy regimen is platinum plus etoposide. (See 'When is chemoradiation used?' below.)
In an observational study of 127 patients with limited-stage small cell esophageal carcinoma, RT plus chemotherapy was associated with improved OS compared with surgery and chemotherapy (three-year OS 50 versus 24 percent) [73]. OS outcomes were especially poor for patients with stage III esophageal NEC who were treated surgically [59,73].
General principles — The following sections outline treatment principles that are generally applicable to the management of localized or locoregionally advanced GEP NEC.
When is chemoradiation used? — The addition of RT to chemotherapy (also known as chemoradiation [CRT]) is used to treat esophageal NEC and individualized for localized or locoregionally advanced NEC arising in other primary tumor locations. Its use in NEC is also extrapolated from the treatment paradigm for limited-stage SCLC where the addition of thoracic RT to chemotherapy improves OS but increases toxicity. (See "Limited-stage small cell lung cancer: Initial management", section on 'Benefit of RT'.)
The rationale for CRT is to control primary tumor burden and reduce the risk of local recurrences. However, since distant recurrences are far more frequent than local recurrences, all patients treated with CRT should also receive chemotherapy with four to six cycles of platinum (either cisplatin or carboplatin) plus etoposide; this regimen is compatible with concurrent RT. Clinical scenarios where CRT may be offered are as follows:
●High risk of local recurrence – Adjuvant or neoadjuvant CRT is reasonable if the risk of local recurrence is thought to be higher than average (eg, T3 to T4 rectal tumors) [51] or if there are positive surgical margins on resection [48].
●Other scenarios – CRT is also a reasonable option for esophageal NEC, locoregionally advanced disease (T3 to T4 and/or lymph node-positive), or unresectable disease. In these various scenarios, CRT can be administered as definitive therapy (if surgery is not feasible) or neoadjuvant therapy (if surgical resection is feasible).
●Concurrent administration of chemotherapy and RT – If RT and chemotherapy are being administered concurrently, RT is typically initiated during cycles 1 or 2 of chemotherapy. This approach is based on the treatment paradigm for limited-stage SCLC. (See "Limited-stage small cell lung cancer: Initial management", section on 'Preference for concurrent rather than sequential treatment'.)
No role for prophylactic cranial irradiation — We do not offer prophylactic cranial irradiation (PCI) to patients with localized GEP NEC and no clinical evidence of central nervous system (CNS) metastases. Data on extrapulmonary NEC suggest a lower frequency of CNS metastases than seen with pulmonary SCLC [27-29]. (See "Prophylactic cranial irradiation for patients with small cell lung cancer".)
INITIAL TREATMENT OF METASTATIC DISEASE —
GEP NEC is an aggressive cancer that is characterized by rapid disease progression and early widespread metastases. As a result, metastatic GEP NEC is typically treated with systemic therapy. Although the goals of treatment are palliative and not curative, systemic therapy reduces cancer-related symptoms and improves quality of life and overall survival (OS) [19]. Given the rapidly progressive nature of these tumors, immediate referral to medical oncology for initiation of systemic therapy is necessary. Clinical trial enrollment is encouraged, where available.
Selection of initial therapy — For patients with metastatic GEP NEC, we suggest initial therapy with platinum (either carboplatin or cisplatin) plus etoposide rather than other chemotherapy regimens. Appropriate alternatives include cisplatin plus irinotecan, FOLFOX, or FOLFIRINOX.
Chemotherapy with platinum (either cisplatin or carboplatin) plus etoposide was initially adopted as the standard first-line treatment for metastatic GEP NEC due to their similarities to small cell lung cancer (SCLC) that is standardly treated with platinum plus etoposide-based regimens. Cisplatin plus irinotecan is also a regimen that is effective against SCLC. However, NEC that originate in the GEP tract can be molecularly similar (and possibly share stem cells of origin) with adenocarcinomas of their corresponding primary sites. Thus, it is possible that regimens that are active in gastrointestinal (GI) cancers, such as fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) may also be similarly or even more effective than platinum plus etoposide in GEP NEC. Further randomized studies are necessary to compare these regimens and determine the optimal treatment approach.
Platinum plus etoposide — For patients who are receiving platinum plus etoposide as initial therapy, cisplatin plus etoposide and carboplatin plus etoposide are both equally appropriate options with likely similar efficacy, and selection of therapy is mainly based on toxicities. Cisplatin plus etoposide has a higher risk of nephrotoxicity, neuropathy, ototoxicity, and emesis. In contrast, carboplatin plus etoposide has a higher risk of hematologic toxicity, mucosal toxicity, and interstitial pneumonitis.
We typically administer four to six cycles of chemotherapy with platinum plus etoposide, followed by close surveillance for disease progression with history, physical examination, and imaging studies every three months (typically a contrast-enhanced CT of the chest, abdomen, and pelvis) [74]. For patients who complete six cycles and are still responding to and tolerating treatment well, it is appropriate to continue chemotherapy until disease progression and/or treatment intolerance.
Most studies in metastatic GEP NEC have focused on initial chemotherapy with platinum plus etoposide, using a similar management strategy to SCLC where there are high-quality data for this approach. In observational studies of metastatic GEP NEC, the objective response rates (ORRs) for cisplatin or carboplatin plus etoposide ranges between 30 and 50 percent [19,26,34,75]. Unfortunately, these responses are not durable, and almost all patients eventually relapse and die of their disease. (See "Extensive-stage small cell lung cancer: Initial management", section on 'Rationale for platinum-etoposide as choice of chemotherapy'.)
As examples:
●In a retrospective study (NORDIC NEC), 252 patients with advanced GEP NEC were treated with either cisplatin or carboplatin plus etoposide [19]. Among those receiving this combination as first-line chemotherapy, the ORR was 31 percent, with median progression-free survival (PFS) and OS of 4 and 11 months, respectively. No significant differences in outcomes were observed with the use of cisplatin versus carboplatin.
●In another retrospective series of 123 patients with metastatic GEP NEC who received first-line treatment with platinum plus etoposide, the ORR and stable disease rates were 50 and 23 percent [26]. Median PFS and OS were 6 and 12 months, respectively.
Platinum plus irinotecan — Platinum (either cisplatin or carboplatin) plus irinotecan is another option for initial therapy in metastatic GEP NEC. In a phase III trial, cisplatin plus irinotecan was similarly effective to cisplatin plus etoposide but with lower rates of severe febrile neutropenia [76].
Based on data from a randomized phase II trial [77], an open-label phase III trial (TOPIC-NEC) was conducted to compare cisplatin plus irinotecan with cisplatin plus etoposide in 170 patients with systemic therapy-naïve recurrent or unresectable digestive NEC [76]. At a median follow-up of two years, OS was similar between the two treatment arms (median OS 12.5 versus 10.9 months, hazard ratio [HR] 1.04, 95% CI 0.79-1.37). Grade 3 and 4 toxicity rates were higher with cisplatin plus etoposide relative to cisplatin plus irinotecan for neutropenia (92 versus 54 percent), leukopenia (61 versus 31 percent), and febrile neutropenia (27 versus 12 percent). However, the incidence of febrile neutropenia due to cisplatin plus etoposide was reduced when the protocol was revised to introduce the prophylactic use of granulocyte colony stimulating factors.
FOLFOX — The use of FOLFOX as initial therapy for metastatic GEP is extrapolated from studies evaluating this regimen as second- and later-line therapy [26,78]. These studies are discussed separately. (See 'FOLFOX' below.)
FOLFIRINOX — In a retrospective in a heterogeneous population of 35 patients with high-grade neuroendocrine neoplasms (NENs; primarily with NEC or metastatic disease), initial therapy with FOLFIRINOX demonstrated an ORR of 77 percent [79].
Is there a role for combining immunotherapy and chemotherapy? — For metastatic GEP NEC, there is no established role for the addition of an immune checkpoint inhibitor (ICI) to initial platinum-based chemotherapy. Although this combination is used to treat extensive-stage SCLC, there are limited data for this approach in metastatic GEP [80,81], and further randomized trials are necessary. (See "Extensive-stage small cell lung cancer: Initial management", section on 'Preferred option: Immunotherapy plus platinum-etoposide'.)
In a single-arm, open-label phase II trial (NICE-NEC), 38 patients with systemic therapy-naïve grade 3 NEN of GEP or unknown origin received nivolumab in combination with up to six cycles of carboplatin and etoposide, followed by maintenance nivolumab [81]. In preliminary results, at a median follow-up of 19 months, the ORR was 54 percent. Median PFS and OS were 6 and 14 months, respectively.
SUBSEQUENT THERAPY FOR METASTATIC DISEASE —
For patients with metastatic GEP NEC who progress after initial systemic chemotherapy, there are limited data for the optimal management strategy for second- and later-line therapy. Patients who are ineligible for further systemic therapy (eg, poor Eastern Cooperative Oncology Group performance status (table 9), multiple or poorly-controlled comorbidities) may be offered best supportive care.
Actionable molecular alterations — The management of patients whose tumors harbor an actionable molecular alteration on somatic tumor testing is discussed in the specific sections below. (See 'Somatic tumor tissue testing' above.)
dMMR/MSI-H tumors — For patients with metastatic GEP NEC who progress on initial chemotherapy and whose tumors express mismatch repair deficiency (dMMR)/high microsatellite instability (MSI-H), we suggest second-line therapy with an immune checkpoint inhibitor (ICI) rather than other systemic agents, as data suggest durable responses with this approach. Options include pembrolizumab and dostarlimab.
Deficient mismatch repair (dMMR), the biologic footprint of which is MSI-H, is present in approximately 5 percent of patients with GEP NEC, most frequently in those with colorectal primaries [39,82,83].
●Pembrolizumab – In a phase II trial (KEYNOTE-158, Cohort K), pembrolizumab was evaluated in 351 previously treated advanced noncolorectal dMMR/MSI-H solid tumors, including 12 patients with neuroendocrine tumors (NETs). Objective responses were seen in two patients (17 percent), with a median duration of response of 13 months [84,85].
●Dostarlimab – The efficacy of dostarlimab in dMMR/MSI-H solid tumors is discussed separately. (See "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Dostarlimab'.)
Both pembrolizumab and dostarlimab have received a "tissue-agnostic" drug approval from the US Food and Drug Administration (FDA) due to their efficacy across a wide array of solid tumor histologies expressing dMMR/MSI-H [84].
TMB-H tumors — For those with metastatic GEP NEC who progress on initial chemotherapy and whose tumors express high tumor mutational burden (TMB-H; ≥10 mutations per megabase), we offer second-line therapy with ICIs. Options include single-agent pembrolizumab or the combination of nivolumab plus ipilimumab, although data are limited for the latter [86].
●Pembrolizumab – The efficacy of pembrolizumab was established in an open-label, single-arm phase II trial (KEYNOTE-158) of over 1000 patients with a variety of advanced unresectable or metastatic solid tumors who had progressed on or were unable to tolerate at least one prior line of systemic therapy [87]. A subset of 102 patients had TMB-H tumors (defined as TMB ≥10 mutations per megabase). At a median follow-up of 37 months, among the patients with TMB-H NETs, the objective response rate (ORR) was 40 percent. Median duration of response was not reached in the entire TMB-H group (range 2 to 35 months or longer). Further details of this study are discussed separately. (See "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Pembrolizumab'.)
●Nivolumab plus ipilimumab – Data are limited for the efficacy of nivolumab plus ipilimumab in TMB-H metastatic GEP NEC. A retrospective study of 70 patients with metastatic, platinum plus etoposide refractory extrapulmonary NEC predominantly of GEP origin included a subgroup of 11 patients who were treated with dual ICI therapy (eg, nivolumab plus ipilimumab) [86]. In this subgroup of patients treated with dual ICI therapy, median progression-free survival (PFS) and overall survival (OS) were 258 days (approximately nine months) and not reached, respectively. Although genomic data were limited, there were no significant differences in treatment outcomes according to TMB status [86].
BRAF V600E-positive tumors — BRAF V600E mutations are found in 50 percent of metastatic colorectal NEC [39].
For patients with metastatic GEP NEC who progress on initial chemotherapy and whose tumors test positive for a BRAF V600E mutation, we offer chemotherapy using the same approach as those without an actionable molecular alteration. (See 'No actionable molecular alterations' below.)
For those who progress on or are ineligible for further chemotherapy, we suggest dabrafenib plus trametinib rather than other systemic agents. Based on data from a multicohort basket trial (NCI-MATCH), this combination is effective with an acceptable toxicity profile and can be administered orally for patient convenience [88]. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)
Dabrafenib plus trametinib has accelerated approval from the FDA for patients with any unresectable or metastatic solid tumor with a BRAF V600E mutation who have progressed on prior therapy and have no satisfactory alternative treatment options [84].
Less common mutations
TRK fusion-positive tumors — For patients with metastatic GEP NEC who progress on initial chemotherapy and have tropomyosin receptor kinase (TRK) fusion positive-tumors, we offer a TRK inhibitor. Options include either entrectinib, larotrectinib, or repotrectinib. In phase I/II basket trials in advanced NTRK-gene fusion-positive tumors of various cancer types, entrectinib, larotrectinib, and repotrectinib all demonstrate high ORRs that are durable [84,89,90]. Further details of these studies are discussed separately. (See "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'TRK inhibitor activity'.)
Larotrectinib, entrectinib, and repotrectinib are approved by the FDA for the treatment of patients with solid tumors that have an NTRK-gene fusion, who have metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or have progressed following treatment [84].
RET fusion-positive tumors — For patients with metastatic GEP NEC who progress on initial chemotherapy and have RET fusion-positive tumors, we offer second-line chemotherapy using the same approach as those without an actionable molecular alteration. (See 'No actionable molecular alterations' below.)
For those who progress on or are ineligible for further chemotherapy, we suggest selpercatinib rather than other systemic agents. In a phase I/II basket trial (LIBRETTO-001) in treatment-refractory RET fusion-positive tumors of various cancer types, selpercatinib demonstrated an ORR of 44 percent [91].
Selpercatinib has accelerated approval from the FDA for the treatment of adult patients with locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options [84].
No actionable molecular alterations — For patients without an actionable molecular alteration or those who are ineligible for targeted therapy, selection of second- and later-line therapy is based on the previous therapies received and the rapidity of disease progression.
Prior platinum plus etoposide — For patients with metastatic GEP NEC who progress six months or more after discontinuing initial platinum plus etoposide and have no actionable mutations, we suggest retreating with platinum plus etoposide rather than other systemic agents. Administration of a chemotherapy regimen not previously received is also a reasonable alternative. (See 'Other chemotherapy regimens' below.)
In a retrospective study (NORDIC NEC) of patients with advanced GEP NEC who progressed on initial platinum-based chemotherapy, retreatment with the same platinum-based regimen yielded an ORR and stable disease rate of 15 and 27 percent, respectively [19].
For patients with progress within six months after discontinuing initial treatment with platinum plus etoposide and have no actionable mutations, we suggest chemotherapy not previously received rather than retreating with platinum plus etoposide due to likely tumor resistance. Options include irinotecan-based regimens, oxaliplatin-based regimens, or temozolomide with or without capecitabine. (See 'Other chemotherapy regimens' below.)
Prior cisplatin plus irinotecan or fluorouracil (FU)-based chemotherapy — For patients who progress on initial treatment with platinum plus irinotecan, FOLFOX, or FOLFIRINOX and have no actionable mutations, options for second-line therapy include either platinum plus etoposide or a chemotherapy regimen not previously received. (See 'Other chemotherapy regimens' below.)
Other chemotherapy regimens — Chemotherapy options for second- and later-line therapy include irinotecan-based regimens, oxaliplatin-based regimens, and temozolomide with or without capecitabine. Patients are generally given chemotherapy agents not previously received.
FOLFIRI — FOLFIRI has been evaluated as second- and later-line therapy in platinum-refractory metastatic GEP NEC, with ORRs of up to 31 percent. [26,92-94]. As examples:
●In a randomized phase II trial of 53 patients with metastatic NEC (with a GEP, lung, or other primary site) who progressed on initial platinum-based chemotherapy, second-line therapy with either FOLFIRI or capecitabine plus temozolomide resulted in similar OS (one-year OS 28 versus 32 percent), PFS (median three months each), and partial response rates (17 versus 12 percent) [94]. The 12-week disease control rates were 39 and 28 percent, respectively. However, the study was closed early for futility as the 12-week disease-control rate threshold was not reached.
●In a phase II trial (PRODIGE 41-BEVANEC), 150 patients with locally advanced or metastatic GEP NEC or NEC of unknown primary who progressed on initial treatment with platinum plus etoposide were randomly assigned to FOLFIRI alone or in combination with bevacizumab [92]. At a median follow-up of 26 months, compared to FOLFIRI alone, FOLFIRI plus bevacizumab improved the ORR (25 versus 18 percent) but failed to improve PFS (median four months for both arms) or OS (median seven versus nine months).
Fluorouracil plus liposomal irinotecan — FU plus liposomal irinotecan has been evaluated as second-line therapy in platinum-refractory metastatic GEP NEC. In a phase II trial, 58 patients with poorly differentiated extrapulmonary NEC (69 percent with GEP) who previously received cisplatin-based chemotherapy were randomly assigned to second-line therapy with either FU plus liposomal irinotecan versus docetaxel [95]. At a median follow-up of five months, six-month PFS was higher for FU plus liposomal irinotecan relative to docetaxel. ORR (11 versus 10 percent), PFS (three versus two months), and OS (six months each) were similar between the two treatment arms. Grade ≥3 toxicity rates were also similar (52 versus 55 percent).
Temozolomide with or without capecitabine — Temozolomide with or without capecitabine has been evaluated as second- and later-line therapy in platinum-refractory metastatic GEP NEC [10,94,96-98]. As examples:
●In a randomized phase II trial of 53 patients with metastatic NEC (with GEP, lung, or other primary site) who progressed on initial platinum-based chemotherapy, second-line therapy with either capecitabine plus temozolomide or FOLFIRI resulted in similar OS (one-year OS 32 versus 28 percent), PFS (median three months each), and partial response rates (12 versus 17 percent) [94]. The 12-week disease control rates were 28 and 39 percent, respectively. However, the study was closed early for futility as the 12-week disease-control rate threshold was not reached.
●In a retrospective study, 130 patients with high-grade (G3) NEN received either capecitabine plus temozolomide (92 percent) or temozolomide alone (8 percent) [98]. Most patients (72 percent) had received at least one line of prior therapy (platinum-based chemotherapy, everolimus, sunitinib, somatostatin analogs). Among the subset of 46 patients (35 percent) with NEC, the ORR was 26 percent. The time to treatment failure was three months and median OS was 13 months.
FOLFOX — FOLFOX has been evaluated as second- and later-line therapy in platinum-refractory metastatic GEP NEC [26,78].
●In a retrospective study, 17 patients with advanced NEC (12 with a GEP primary site) received FOLFOX after progression on cisplatin or carboplatin [78]. At a median follow-up of 19 months, objective responses were seen in five patients, all of which were partial responses (29 percent). Median PFS and OS were 5 and 10 months, respectively.
●In another observational series of 33 patients with GEP NEC who received second- or later-line therapy with FOLFOX after progressing on initial platinum plus etoposide, objective responses were seen in 4 of 24 patients (17 percent), with a median PFS of 2.3 months [26].
FOLFIRINOX — FOLFIRINOX has been evaluated as second- and later-line therapy in metastatic GEP NEC [99,100]. As an example, in one retrospective study, 37 patients with metastatic GEP NEC of varying primary sites (colon, pancreas, esophagus, and rectum) were treated with FOLFIRINOX, mostly as second-line therapy (57 percent) [100]. In the entire population, the ORR was 46 percent. Median PFS and OS were 5 and 18 months, respectively.
Later-line therapy
Nivolumab plus ipilimumab — Nivolumab plus ipilimumab is a later-line option for patients with metastatic GEP NEC who progress on multiple systemic therapies and have not previously received immunotherapy. Although combination immunotherapy demonstrates modest ORRs, some patients can achieve durable disease control [101-105]. We do not offer single-agent immunotherapy, which has minimal efficacy in unselected patients with metastatic GEP NEC [86,106-109].
●In a phase II basket trial (SWOG S1609 DART), nivolumab plus ipilimumab was evaluated in 19 patients with treatment-refractory, microsatellite stable high-grade NEN (median Ki-67 80 percent) of various primary sites (rectum, gastroesophageal junction, cervix, pancreas, and unknown) [101]. The ORR was 26 percent, with median PFS and OS of two and nine months, respectively.
●In a randomized phase II NIPINEC trial, 185 patients with platinum-refractory disease (93 with GEP NEC and 92 with lung NEC) were randomly assigned to either nivolumab plus ipilimumab or nivolumab monotherapy [103]. In preliminary results, relative to nivolumab alone, nivolumab plus ipilimumab increased the ORR at eight weeks (14.9 versus 7.2 percent) but failed to improve PFS (median 1.9 versus 1.8 months) or OS (median 5.8 versus 7.2 months).
SPECIAL POPULATIONS
Mixed neuroendocrine-non-neuroendocrine neoplasms — There is clinical variability in the initial management of patients with metastatic mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) due to limited high-quality data. In general, such tumors are treated using the same management approach as pure GEP NEC. For patients with a MiNEN and an NEC as the neuroendocrine component, some studies suggest using platinum plus etoposide [110]. However, regimens used to treat gastrointestinal (GI) cancers, such as FOLFOX or FOLFIRINOX, are also appropriate, although data are limited [111].
PROGNOSIS —
GEP NEC has a poor prognosis. These tumors progress rapidly and have a high proclivity for metastatic dissemination, even in the setting of localized disease.
Stage — Although prognosis is generally poor for all stages of disease, localized disease is associated with a much better overall survival (OS) compared with advanced or metastatic disease [1,13,17,19,23,24,26,112]. In an observational study from the Surveillance, Epidemiology, and End Results (SEER) database, five-year OS for localized, regional, and metastatic GEP NEC were 42, 26, and 5 percent, respectively [17].
●Localized disease – Long-term survival is possible among patients with localized disease who are treated with multimodality therapy [17,51]. In one observational series of patients with stage I, II, or III GEP NEC, five-year OS was approximately 30 percent and was best in those with colonic primaries (five-year OS of 40 percent) [51]. In another observational study that included patients with localized and locoregionally advanced gastrointestinal (GI) NEC treated with the combination of surgery and systemic therapy, five-year OS was 42 and 26 percent, respectively, with some differences according to the primary tumor site [17].
●Advanced and metastatic disease – Prognosis is worse for advanced and metastatic disease. In a retrospective study (NORDIC NEC), 252 patients with advanced GEP NEC were treated with chemotherapy [19]. In the cohort receiving chemotherapy, two- and three-year OS were 14 and 10 percent, respectively.
While most studies report no difference in prognosis between the large cell and small cell subtypes of GEP NEC [24,113-116], others suggest that the large cell subtype is associated with improved survival compared with the small cell subtypes [1,17].
Primary tumors in the esophagus or large bowel carry a worse prognosis than those in the stomach or pancreas [19,20,117]. Prognosis is especially poor for those whose primary tumor site is the large bowel. Even with aggressive therapy that includes platinum-based systemic chemotherapy, there are only rare reports of long-term survivors [55,112,118-121].
Other factors — Other clinical factors associated with a poor prognosis include poor performance status [19,20,26,122], higher Ki-67 proliferation rate [19,78,97,122-124], elevated lactate dehydrogenase and other tumor markers [19,20,26], and thrombocytosis [19]. In contrast to GI and pancreatic adenocarcinoma, molecular alterations such as BRAF V600E mutations do not generally predict prognosis in metastatic GEP NEC [125,126].
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuroendocrine neoplasms".)
SUMMARY AND RECOMMENDATIONS
●Definition – Poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (ie, GEP NEC) are neuroendocrine neoplasms (NENs) arising from the gastrointestinal (GI) tract or pancreas that exhibit poor histologic differentiation and are always high-grade (grade 3) (table 1). (See 'Definition' above.)
●Clinical presentation
•Primary tumor site – Colorectal primary tumors account for most GEP NEC, followed by upper GI and pancreatic primary tumors. Small bowel primary tumors are rare. (See 'Primary tumor site' above.)
•Metastatic disease – Most patients present with metastatic disease (50 percent or more) due to the aggressive nature of this disease. Common sites of metastases include liver, bone, and lungs. The risk of brain metastases is much lower in GEP NEC than small cell lung cancer (SCLC). Nearly all tumors are nonfunctional (ie, not hormone-secreting) due to the poorly differentiated state of the tumor. (See 'Symptoms of metastatic disease' above.)
●Diagnostic evaluation
•Diagnosis – The diagnosis of a GEP NEC is confirmed based on histopathologic evaluation of tumor tissue, either from a biopsy or surgically excised specimen. GEP NEC is classified as either small cell type NEC or large cell type NEC (figure 1). Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) typically have components of a poorly differentiated NEC. (See 'Tissue specimen (diagnosis)' above and "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms".)
•Imaging studies – All patients should undergo a contrast-enhanced CT of the chest, abdomen, and pelvis to assess the extent of disease. For patients who are being evaluated for surgery, we also obtain a fluorodeoxyglucose-positron emission tomography (FDG-PET)-CT to exclude metastatic disease prior to resection. We do not routinely obtain central nervous system (CNS) imaging in patients lacking neurologic symptoms or somatostatin receptor (SSTR)-based imaging. (See 'Imaging studies' above.)
•Somatic tumor tissue testing – Patients with advanced or metastatic disease should be tested for actionable mutations using next-generation sequencing (NGS) on a tumor tissue sample. For patients with inadequate or unavailable tissue samples, actionable mutations can be identified through cell-free DNA testing. (See 'Somatic tumor tissue testing' above.)
●Staging – GEP NEC are staged using the same American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system that is used for adenocarcinomas at the individual primary tumor sites such as the esophagus (table 2), stomach (table 3), pancreas (table 4), gallbladder (table 5), small bowel (table 6), colon or rectum (table 7), and anal canal (table 8).
●Treatment of locoregional disease
•Non-esophageal primary GEP NEC
-Localized resectable disease – For patients with a non-esophageal primary GEP NEC (ie, colorectal, gastric, gallbladder, pancreatic) that is localized (T1 to T2N0) and resectable, we suggest surgical resection plus adjuvant chemotherapy rather than surgery alone (Grade 2C). Neoadjuvant chemotherapy followed by surgery is also an appropriate alternative, especially for patients with a high-estimated risk of postoperative morbidity where adjuvant treatment may be delayed. (See 'Non-esophageal NEC' above.)
-Locoregionally advanced, resectable disease – For those with locoregionally advanced (T3 to T4 and/or lymph node-positive) resectable disease, we suggest neoadjuvant chemotherapy (with or without concurrent radiation therapy [RT]) followed by surgery rather than surgery alone (Grade 2C), given the aggressive nature of NEC. For patients with tumor sites that are resectable but at high risk for surgical morbidity (eg, distal rectum, pancreatic head), definitive chemoradiation (CRT) is an option, but surgery is likely still needed to achieve appropriate overall survival (OS) outcomes.
-Unresectable disease – For those with unresectable locoregional disease, we suggest the combination of chemotherapy and RT (administered either concurrently or sequentially) rather than either modality alone (Grade 2C). Systemic therapy, however, is also an appropriate alternative. (See 'Non-esophageal NEC' above.)
•Esophageal primary – For patients with a localized or locoregionally advanced esophageal primary NEC (regardless of resectability), we suggest RT plus chemotherapy rather than surgery plus chemotherapy (Grade 2C). Chemotherapy and RT can be administered either concurrently or sequentially.
•General principles
-Selection of chemotherapy agents – For all patients with a localized or locoregional GEP NEC (regardless of the primary tumor site), we offer chemotherapy with platinum (either cisplatin or carboplatin) plus etoposide. In most cases, chemotherapy is administered in the neoadjuvant setting. (See 'Neoadjuvant chemotherapy' above.)
-When is chemoradiation used? – The addition of RT to chemotherapy (ie, CRT) is used to treat esophageal NEC and individualized for NEC arising from other primary sites. The rationale for RT is to control primary tumor burden and reduce the risk of local recurrences. All patients treated with CRT should also receive chemotherapy with four to six cycles of platinum (either cisplatin or carboplatin) plus etoposide due to the risk of distant metastases; this regimen is compatible with concurrent RT.
-No role for PCI – We do not offer prophylactic cranial irradiation (PCI) to patients with localized GEP NEC and no clinical evidence of CNS metastases. (See 'No role for prophylactic cranial irradiation' above.)
●Treatment of metastatic disease – Metastatic GEP NEC is typically treated with systemic therapy due to the aggressive nature of these tumors. The goals of treatment are palliative and not curative. Clinical trial enrollment is encouraged, where available.
●Initial therapy for metastatic disease – For patients with metastatic disease, we suggest initial therapy with platinum (either carboplatin or cisplatin) plus etoposide rather than other chemotherapy regimens (Grade 2C). Appropriate alternatives include platinum plus irinotecan, FOLFOX, or FOLFIRINOX. (See 'Selection of initial therapy' above.)
●Subsequent therapy for metastatic disease – For patients with metastatic disease who progress after initial systemic chemotherapy, the approach to second- and later-line therapy is as follows:
•dMMR/MSI-H tumors – For patients whose tumors express mismatch repair deficiency (dMMR)/high microsatellite instability (MSI-H), we suggest second-line therapy with an immune checkpoint inhibitor (ICI) rather than other systemic agents (Grade 2C), as data suggest durable responses with this approach. Options include pembrolizumab or dostarlimab. (See 'dMMR/MSI-H tumors' above and "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Treatment'.)
•TMB-H tumors – For patients whose tumors express high tumor mutational burden (TMB-H; ≥10 mutations per megabase), we offer ICIs. Options include single-agent pembrolizumab or nivolumab plus ipilimumab. (See 'TMB-H tumors' above and "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Treatment'.)
•BRAF V600E mutated tumors – For patients whose tumors test positive for a BRAF V600E mutation, we offer second-line chemotherapy using the same approach as those without an actionable molecular alteration. (See 'No actionable molecular alterations' above.)
For those who progress on or are ineligible for further chemotherapy, we suggest dabrafenib plus trametinib rather than other systemic agents (Grade 2C). (See 'BRAF V600E-positive tumors' above.)
•TRK fusion-positive tumors – For patients with tropomyosin receptor kinase (TRK) fusion-positive tumors, we offer second-line therapy with a TRK inhibitor. Options include entrectinib, larotrectinib, or repotrectinib. (See 'TRK fusion-positive tumors' above and "TRK fusion-positive cancers and TRK inhibitor therapy", section on 'TRK inhibitor activity'.)
•RET fusion-positive tumors – For patients with RET fusion-positive tumors, we offer second-line chemotherapy using the same approach as those without an actionable molecular alteration. (See 'No actionable molecular alterations' above.)
For those who progress on or are ineligible for chemotherapy, we suggest selpercatinib rather than other systemic agents (Grade 2C). (See 'RET fusion-positive tumors' above.)
•No actionable molecular alterations – For patients without an actionable molecular alteration or those who are ineligible for targeted therapy, selection of therapy is based on prior therapy and the rapidity of disease progression:
-Prior platinum plus etoposide – For those who progress six months or more after discontinuing initial platinum plus etoposide, we suggest retreating with platinum-based chemotherapy rather than other systemic agents (Grade 2C). A chemotherapy regimen not previously received is also a reasonable alternative. (See 'Prior platinum plus etoposide' above.)
For patients who progress within six months after discontinuing initial treatment with platinum plus etoposide, we suggest second-line treatment with a chemotherapy regimen not previously received rather than retreating with platinum plus etoposide (Grade 2C) due to likely tumor resistance. Options include irinotecan-based regimens, oxaliplatin-based regimens, or temozolomide with or without capecitabine. (See 'Other chemotherapy regimens' above.)
•Later-line therapy – Nivolumab plus ipilimumab is a later-line option for those who progress on multiple systemic therapies and have not previously received immunotherapy. (See 'Nivolumab plus ipilimumab' above.)
