Background
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous malignancies arising from neuroendocrine cells.1 High-grade tumors are characterized by high proliferation rate (Ki-67 >20%) and comprise both well-differentiated grade 3 (G3) neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs).2 Gastroenteropancreatic NECs (GEP-NECs) may contain a non-neuroendocrine component, including adenocarcinoma, signet ring cell carcinoma, or squamous cell carcinoma, and should be referred to as mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs) when both the neuroendocrine and non-neuroendocrine component exceed the 30% of the tumor composition.3 G3 NETs and NECs have distinct molecular features,4 and survival durations are more than double in patients with well-differentiated tumors compared with poorly differentiated carcinomas.5,6 Although chemotherapy, targeted agents, and somatostatin analogs may show clinical efficacy against G3 NETs, chemotherapy remains the only therapeutic option for the treatment of NECs as well as MiNENs with a poorly differentiated neuroendocrine component.7–9 In this context, the combination of platinum and etoposide represents the standard first-line therapy in patients with advanced NECs, with reported objective response rates (ORRs) ranging from 15% to 50% and median response durations of up to 9 months.10
5-FU, irinotecan, and platinum compounds show substantial antitumor activity against high-grade GEP-NENs. In a randomized phase III trial of 170 patients with high-grade NENs, first-line etoposide/platinum and irinotecan/cisplatin achieved similar results in terms of survival outcomes.11 Moreover, irinotecan-based regimens recently showed signs of activity in the second-line treatment of patients with NECs in the context of the NET-02 and BEVANEC trials.12,13 Chemotherapy regimens such as FOLFOX (leucovorin, 5-FU, and oxaliplatin), CAPOX (capecitabine and oxaliplatin), and FOLFIRI (leucovorin, 5-FU, and irinotecan) are preferred second-line therapies in patients with NEC progressing on an etoposide/platinum doublet, and are commonly used in other high-grade NENs in any lines of treatment.14–17
Chemotherapeutic regimens comprising 5-FU, irinotecan, and oxaliplatin (ie, FOLFIRINOX, mFOLFIRINOX, or FOLFOXIRI) are routinely administered for the treatment of several digestive cancers, including pancreatic ductal adenocarcinoma and colorectal adenocarcinoma.18,19 In a small case series of 2 pancreatic NECs, the mFOLFIRINOX triplet demonstrated antitumor activity in the presence of a manageable toxicity profile.20 Preliminary findings from a retrospective study of 37 patients with GEP-NEC treated with FOLFIRINOX as first or subsequent line of treatment showed an ORR of 46%.21 In the present study, we retrospectively assessed the safety and efficacy profile of first-line mFOLFIRINOX chemotherapy in patients with advanced G3 NETs, NECs, and MiNENs of GEP origin treated at 3 high-volume institutions.
Patients and Methods
Patients and Treatment
Approval for data collection and analysis was obtained from the Ethical Committee of each participating center. A waiver of consent was granted due to the study’s retrospective nature. We reviewed the records of adult patients (age >18 years) with unresectable G3 NET, NEC, or MiNEN with a poorly differentiated neuroendocrine component of the GEP tract or of unknown origin who were treated with first-line mFOLFIRINOX between February 2016 and April 2023 at University and Hospital Trust of Verona, University Hospital of Bari, and Moffitt Cancer Center. All patients gave their informed consent to the treatment according to each center’s requirements. Demographic, clinical, and pathologic information, including age, sex, ECOG performance status (PS), primary tumor site, tumor grade by WHO 2019 criteria,2 Ki-67 labeling index, date of treatment initiation, date of treatment completion, and date of last follow-up or death were obtained through review of patient medical records. Chemotherapy starting doses, dose reductions, interruptions, toxicities at least possibly associated with treatment, and reasons for chemotherapy discontinuation were also collected. Toxicities were graded using CTCAE version 5.0. The chemotherapy regimen18 consisted of oxaliplatin, 85 mg/m2 intravenously; leucovorin, 400 mg/m2 intravenously; irinotecan, 150 mg/m2 intravenously; and 5-FU, 2,400 mg/m2 over a 46-hour infusion (without bolus 5-FU) administered every 14 days until progression or intolerable toxicity.
Outcomes
Assessments of radiographic response were performed by study investigators. The nearest pretreatment CT or MRI scan was used as baseline and compared with subsequent scans obtained as part of routine clinical care (approximately every 3 months). RECIST version 1.1. was used for evaluation of radiographic response.22 Progression-free survival (PFS) was defined as the time from chemotherapy initiation to radiologic progression or death from any cause. Overall survival (OS) was measured from the date of treatment start until death due to any cause, with patients censored at the date of the last follow-up if still alive.
Statistical Analysis
Descriptive statistics were used for patient demographics. The distribution of covariates was compared across groups using Fisher test for categorical variables. The Wilcoxon-matched pairs signed-rank test was used to assess differences in the concentration of tumor markers at diagnosis and at the time of radiologic best response. Time-to-event functions were estimated using the Kaplan-Meier method and compared using the log-rank test. Exact 95% confidence intervals were calculated for each proportion of interest. All tests were 2-sided and statistical significance was declared at P<.05. Statistical analysis was performed using MedCalc version 12.7 (MedCalc Software Ltd).
Results
Patient Characteristics
Patient demographics and tumor characteristics are summarized in Table 1. A total of 35 patients met the eligibility criteria for analysis, including 15 females (43%) and 20 males (57%). Median age at diagnosis was 57.5 years (range, 38–75 years). ECOG PS at treatment initiation was 0 in 28 (80%) patients and 1 in 7 (20%) patients. Most patients (n=23; 66%) had a primary pancreatic tumor. Metastases were documented in 30 (86%) patients, whereas 5 (14%) had stage III unresectable neoplasms. Among patients with metastatic disease, the liver was the only metastatic site in 13 (37%), whereas extrahepatic spread was observed in 17 (49%). A total of 25 (71%) patients had NECs, 2 (6%) had G3 NETs, and 8 (23%) had MiNENs (all with a poorly differentiated neuroendocrine component). The median Ki-67 index was 70% (range, 25%–100%), and 14 (40%) and 21 (60%) tumors harbored a Ki-67 <55% or ≥55%, respectively. Tumor lesions were homogenously FDG-positive in 20 of 20 cases with available information, with a median SUVmax of 12 (range, 5.7–21.8) in the lesion showing the highest radiotracer uptake. Somatostatin receptor expression by DOTA-peptides PET/CT was documented in 10 of 19 (53%) patients with available information. In all positive cases, the radiotracer uptake was homogeneous among different lesions. A total of 17 (49%) patients were subjected to both metabolic and receptor imaging. Tumor molecular profiling (in-house academic panels or FoundationOne, Roche) was available for 14 (40%) patients. Mutations of TP53 and RB1 were found in 43% and 36% of patients, respectively. Druggable alterations (germline mutations of BRCA) were observed in 2 patients (14%; 1 esophageal NEC and 1 pancreatic NEC).
Patient Demographics and Clinical Characteristics
Regimen
Starting doses of mFOLFIRINOX components were reduced at baseline in 7 of 35 (20%) patients (Table 2). Thus, the average starting doses of 5-FU, leucovorin, irinotecan, and oxaliplatin were 2,270 mg/m2, 380 mg/m2, 142 mg/m2, and 80 mg/m2. The median duration of treatment was 6 months (range, 3–12 months). Median time to best response was 5 months (range, 2–14.6 months). A dose reduction was required for 14 (40%) patients, and 5 (14%) permanently discontinued the treatment because of toxicity. Toxicities leading to treatment discontinuation included peripheral neuropathy (n=4; 11%) and neutropenia (n=1; 3%). Other reasons for treatment discontinuation included progressive disease (n=14; 40%), shift to maintenance treatment (n=11; 31%), and surgical treatment or definitive radiotherapy (n=5; 14%). A total of 2 (6%) patients remained on active treatment at the time of data cutoff. Granulocyte colony-stimulating factor (G-CSF) stimulation was used in 29 of 35 (83%) patients as primary prophylaxis. Chemotherapy cycles were postponed due to toxicities in 18 of 35 (51%) patients.
Treatment Characteristics
Treatment Efficacy
Table S1 in the supplementary material (available online with this article) summarizes treatment efficacy outcomes according to stage and histopathology. All 35 patients were assessable for radiographic response. When best response to therapy was evaluated, complete response, parial response, stable disease, and progressive disease were documented in 3% (1/35), 74% (26/35), 14% (5/35), and 9% (3/35) of patients, respectively. The waterfall plot analysis (Figure 1A) showed some degree of tumor shrinkage in 30 of 35 patients (86%). Among patients harboring tumors with Ki-67 <55%, the ORR was 79% versus 76% in those with Ki-67 ≥55%. Among patients with stage IV disease (n=30), the ORR was 73%. Among 10 patients with baseline-elevated serum neuron-specific enolase (NSE) levels and subsequent NSE evaluations, all experienced major reductions (>50%) or normalization of the tumor marker at the time of best radiographic response. There was a significant difference between the median NSE concentration and its value at the radiographic best response (P=.006; Figure 1B).
Radiographic and biochemical responses following mFOLFIRINOX chemotherapy. (A) Waterfall plot summarizing the maximum percent change from baseline in the sum of longest diameters of target lesions. Asterisks indicate G3 NET; diamonds indicate stage III tumors. (B) In patients with elevated baseline NSE (n=10), normalization of the tumor marker was observed in 8 of 10 cases (80%). Differences between NSE levels at diagnosis and best radiographic response were statistically significant by Wilcoxon-matched pairs signed-rank test (P=.006).
Abbreviations: G3 NET, grade 3 neuroendocrine tumor; mFOLFIRINOX, modified leucovorin/5-FU/irinotecan/oxaliplatin; NSE, neuron-specific enolase.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.7005
At the time of data cutoff, 23 patients had died and 12 were alive, with a median follow-up of 18 months (range, 3–80 months). Median PFS (mPFS) was 12 months (95% CI, 9.2–16.2; Figure 2A). The 1- and 2-year PFS were 47.1% ± 9% and 14.5% ± 6.6%, respectively. Median OS (mOS) was 20.6 months (95% CI, 17.2–30.6; Figure 2B). When comparing patients with pancreatic versus nonpancreatic tumors, we found that mPFS was 12 months (95% CI, 9.5–21.2) versus 9.2 months (95% CI, 5.8–16.2), respectively (P=.6) and mOS was 21.7 months (95% CI, 19–33.2) versus 13.5 months (95% CI, 9.1–30.6), respectively (P=.3; Figure 2C, D). Patients with G3 NET, NEC, and MiNEN exhibited an mPFS of 15.4 months (95% CI, 8.3–not reached [NR]), 10.5 months (95% CI, 7.9–16.2), and 12.7 months (95% CI, 5.7–22.1), respectively (P=.9), in the presence of an mOS of 21.5 months (95% CI, 13.1–33.2) for NECs, 20.6 months (95% CI, 17.2–30.6) for MiNENs, and not reached (95% CI, 20.6–NR) for G3 NET (P=.6; Figure 2E, F). When comparing patients harboring tumors with Ki-67 <55% versus ≥55%, the mPFS was 14.8 months (95% CI, 8.3–22.6) versus 10.5 months (95% CI, 7.7–16.2), respectively (P=.27), in the presence of an mOS of 25.9 months (95% CI, 13.1–56.2) versus 19 months (95% CI, 13.5–30.6), respectively (P=.2; Figure 2G, H). There was a significant difference in terms of both mPFS (P=.04) and mOS (P=.02) between patients with stage III and stage IV malignancies (Figure 2I, J).
Kaplan-Meier estimates of PFS and OS, respectively, in (A, B) the overall population, by (C, D) primary tumor origin, and by (E, F) histopathology. by (G, H) Ki-67 labeling index, and by (I, J) ENETS stage at time of treatment initiation.
Abbreviations: G3 NET, grade 3 neuroendocrine tumor; MiNEN, mixed neuroendocrine–non-neuroendocrine neoplasm; NEC, neuroendocrine carcinoma; OS, overall survival; PFS, progression-free survival.
Abbreviations: ENETS, European Neuroendocrine Tumor Society; OS, overall survival; PFS, progression-free survival.
Citation: Journal of the National Comprehensive Cancer Network 22, 5; 10.6004/jnccn.2024.7005
After excluding patients with locoregional disease who underwent surgery or definitive radiotherapy after mFOLFIRINOX treatment (n=5), we observed an mPFS of 9.6 months (95% CI, 8.3–16.2) and an mOS of 19 months (95% CI, 13.5–24; data not shown). Among patients with stage IV NEC and MiNEN (n=28), the mPFS was 9.6 months (95% CI, 7.9–14.8) and mOS was 19 months (95% CI, 12–24; data not shown).
Treatments Downstream of mFOLFIRINOX
A total of 11 (31%) patients received maintenance therapies after a median of 12 cycles of mFOLFIRINOX. Maintenance treatments included somatostatin analogs (n=5), FOLFIRI chemotherapy (n=2), capecitabine (n=2), and olaparib (n=2; both patients harbored germline BRCA mutations). The median duration of maintenance therapies was 8 months (range, 1–24 months). A total of 13 (37%) patients received locoregional treatments after mFOLFIRINOX completion. In particular, among the 5 patients with stage III disease, 3 underwent surgery, 1 received definitive radiotherapy, and 1 received both treatments. In this group, after a median follow-up of 32.7 months, 2 of 5 (40%) patients experienced disease recurrence. Among patients with stage IV disease, 6 received stereotactic radiotherapy and 2 underwent resection of liver metastases for oligofocal progression in all cases. Among the 26 patients who experienced progression on mFOLFIRINOX or maintenance treatment during the study, 21 (81%) underwent systemic second-line therapy (Table 2). In the entire cohort, 14 patients did not receive subsequent systemic lines of treatment following mFOLFIRINOX administration: 6 were still on treatment at the time of the analysis, 4 died within 3 months of completion of mFOLFIRINOX treatment, and 4 underwent definitive surgery or radiotherapy and did not require further systemic treatments. Median duration of second-line treatment was 3 months (range, 1–10 months).
Toxicities
Supplementary Table S2 summarizes treatment-emergent adverse effects documented during the treatment. Overall, 30 of 35 (86%) patients experienced any-grade treatment-related toxicities. The incidence of grade 3 or 4 adverse events was 43%. There was a significant difference between the proportion of males and females experiencing grade 3 or 4 adverse events (20% vs 73%, respectively; P=.002; odds ratio, 11 [95% CI, 2.3–53.7]). Among the most common grade 3 or 4 adverse effects were neutropenia (17%), diarrhea (8%), fatigue (5%), thrombocytopenia (5%), and peripheral neuropathy (5%). No treatment-induced deaths were recorded.
Discussion
To our knowledge, this is the first retrospective series reporting on the efficacy and toxicity of frontline mFOLFIRINOX chemotherapy in patients with high-grade GEP-NEN. Overall, we observed an ORR of 77%, an mPFS of 12 months, and an mOS of 20.6 months. In a subcohort of 30 patients with stage IV disease only, the ORR was 73%, in the presence of an mPFS of 9.6 months and mOS of 19 months.
The combination of platinum and etoposide represents the current first-line therapy for patients with poorly differentiated advanced GEP-NENs.8,23,24 Among studies performed using contemporary criteria for response assessment,17,25–28 the platinum/etoposide regimen was associated with an ORR between 14% and 52%, an mPFS ranging from 2 to 7 months, and an mOS ranging from 6 to 16 months. When compared with such historical data, the antitumor activity of mFOLFIRINOX reported in the current study appears promising. Moreover, both the mPFS and mOS observed with mFOLFIRINOX fall outside the confidence intervals of the same survival measures reported in landmark studies of etoposide/platinum, including the NORDIC NEC study (mPFS: 4 months [95% CI, 3.1–4.6]; mOS: 11 months [95% CI, 9.4–12.6])31 and the more recent TOPIC-NEC trial (mPFS: 5.6 months [95% CI, 4.1–6.9]; mOS: 12.5 months [95% CI, 10.3–15.7]),11 thus suggesting superior antitumor activity of mFOLFIRINOX over the platinum-based doublet in patients with high-grade NENs.
Although findings from retrospective series should be interpreted cautiously, particularly when the sample size is limited like in our cohort, mFOLFIRINOX appeared to exert antitumor activity irrespective of tumor proliferation. Indeed, similar efficacy was observed against malignancies with Ki-67 <55% or ≥55%. This contrasts with prior evidence documenting lower response rates in patients with Ki-67 <55% receiving platinum/etoposide chemotherapy,30 and possibly reflects inherent differences in the pharmacodynamics of fluoropyrimidine-based and platinum-based regimens. In this regard, we note that the efficacy of fluoropyrimidines is already well-established for both well- and poorly differentiated NENs with a Ki-67 <55%.8, 23,24,31–33
Notably, all 5 patients with stage III disease included in our cohort derived an objective response from mFOLFIRINOX treatment and could undergo radical surgery, definitive radiotherapy, or both. In particular, we observed 1 complete response and 4 partial responses. After a median follow-up of 32.7 months, 2 of 5 (40%) patients experienced disease recurrence, while 3 remained disease-free after 26, 49, and 77 months after definitive treatment. These figures suggest that mFOLFIRINOX not only is able to effectively induce tumor shrinkage but also may display activity against microscopic disease, leading to long-term disease control when used in the preoperative setting. Well-designed, multicenter clinical trials of neoadjuvant mFOLFIRINOX in high-grade NENs are warranted.
Approximately one-third of patients included in our cohort received maintenance therapies after the completion of mFOLFIRINOX chemotherapy. Median duration of maintenance therapies was 8 months, suggesting that tumor control is also possible with deintensified protocols after an induction phase with mFOLFIRINOX. In this context, we note that among the 14 tumors that had undergone comprehensive molecular profiling, 2 (14%) displayed druggable alterations (1 esophageal NEC and 1 pancreatic NEC). In both cases, a germline mutation of BRCA was documented and olaparib was initiated according to evidence suggesting its efficacy in this setting.34 At the time of writing, both patients are still on treatment after 4 and 8 months, respectively, suggesting that the systematic assessment of high-grade NEN molecular alterations may pave the way to potentially effective treatments.8 This appears particularly important in a group of malignancies characterized by dismal outcomes after discontinuing of frontline treatment. Similar to the recent PRODIGE 41-BEVANEC trial,13 our study’s median duration of second-line treatment was only 3 months, highlighting a critical unmet need in identifying new effective treatment options in this setting.
The toxicity profile of mFOLFIRINOX observed in our study appears consistent with the known side effect profile of the regimen.19,20 Although the detected frequency of grade 3 or 4 adverse events (overall 43%) appears lower than that reported in previous prospective studies of mFOLFIRINOX in other malignancies,19,20 we note that underreporting of toxicities is an inherent weakness of retrospective analyses and may account for this discrepancy. Additional reasons to explain this difference may include a high percentage (80%) of patients with ECOG PS 0 included in this study, a more intensive use of prophylactic filgrastim in our cohort (83% of patients) compared with previous prospective experiences,19,20 and frequent occurrence of dose reductions and treatment delays in our series, with consequent negative modulation of both dose intensity and dose density. Notably, grade 3 or 4 adverse events were significantly more common in females than males in our cohort (P=.002; odds ratio, 11). Sex-dependent personalization of chemotherapy dosages should be further explored. In the meantime, sex-based dosing adjustments of mFOLFIRINOX might be considered among female patients with high-grade NEN.
Our study has several limitations. First, its retrospective nature, limited sample size, and lack of a comparator arm hamper definitive conclusions. Second, a possible selection bias resulting from the enrollment of very fit patients (80% of patients had an ECOG PS of 0) cannot be excluded. Third, the lack of a fixed schedule of imaging assessment may have led to overestimation of efficacy outcomes. Fourth, the inclusion of stage III and IV NECs, G3 NETs, and MiNENs may confound the interpretation of the overall analysis, with subanalysis being not powered enough to draw reliable conclusions.
Conclusions
mFOLFIRINOX has antitumor activity against high-grade NENs. The efficacy appears similar irrespective of the tumor proliferative activity, although larger cohorts are needed to validate our findings. Sex-based dosing of mFOLFIRINOX should be considered, because most toxicities occur in females. The randomized, phase II FOLFIRINEC trial35 will shed light on the possible superiority of mFOLFIRINOX versus platinum/etoposide in patients with digestive NEC.
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