Special Consideration: Which Biomarker
A recent study analyzed genomic profiling on tumor samples along with nongenomic biomarkers, including circulating CgA and NSE levels, from patients enrolled in the RADIANT-2, RADIANT-3 and RADIANT-4. Lung NET patients showed a significant correlation between PFS and chromosomal aberrations, in particular LOH in chromosome 3. This correlation was still significant after adjusting for tumor grade and baseline circulating levels of CgA and NSE.66
Studies selected in this review did not assess the potential prognostic or predictive role of soluble angiogenic biomarkers (VEGFR1, PIGF), as performed in the RADIANT-3 in the advanced pancreatic NET population.67 In a recent study68 higher baseline neutrophil-lymphocyte ratio (NLR) and lower (lymphocyte-monocyte ratio) LMR correlate with a shorter PFS in patients treated with EVE in NET population of the RADIANT-3 and RADIANT-4 trials. However in the lung subgroup analysis there was no trend observed, possibly due to the small number of patients in the group. A blood mRNA-based biomarker, the NETest, has been proposed as a multianalyte algorithmic tool for lung NET and may represent a promising strategy to establish a diagnosis and monitor therapeutic efficacy.69
Special Consideration: Which Timing for EVE
A post hoc analysis of the RADIANT-4 reported the effect of prior therapies on EVE activity demonstrating that EVE improved outcomes regardless of prior treatments. The safety profile of EVE was not impacted by the use of prior lines of therapies and was similar to that reported for the overall population analysis.70
In addition, limited retrospective studies showed data about sequence of therapies in mixed NET populations, including small number of patients with lung NET.27,32,71,72 Faggiano et al, suggested sequences with first-line SSA followed by SSA high-dose or PRRT as second-line treatment for mixed population NETs. Furthermore chemotherapy and targeted therapy should be then considered in case of further progression because of their worse tolerability.71 Panzuto et al performed a real-world analysis of NET patients treated with EVE suggesting that EVE should be planned before PRRT and chemotherapy to avoid predictable severe toxicities.72
Finally, the last two retrospective analyses were focused on lung NETs and provided an overview of the real-life clinical practice.27,32 Because of long recruitment period and consequent heterogeneity of patient management, the comparison between treatment strategies is precluded. Of note SSAs were the most commonly performed first-line therapy.
No absolute indication about the EVE timing in lung NET can be drawn from our analysis.
The European medicines agency (EMA) approved EVE in lung NETs with progressive disease without a restriction to a subgroup or a specific line of treatment.
As suggested in the ENETS guidelines EVE may be recommended as a first-line therapy in advanced lung NET with progressive disease. However, in patients with low proliferative activity (G1, typical carcinoid) with strong SSTR expression on imaging, preferably with Ki-67 <10%, an SSA may be preferred to EVE as first-line therapy (Table 3).
The same guidelines reported that temozolomide-based chemotherapy may be considered in NET G3 and in high-risk pulmonary NET.73
Special Consideration: Effect on Tumor Shrinkage
Tumor shrinkage can be a goal in case of future surgical approach or mass-effect symptoms control. Data about tumor shrinkage, in lung NET treated with EVE are reported in Table 4. Everolimus is not considered a strong cytoreductive drug in NETs more in general. Similarly in lung NETs, the reported partial response (PR) rate is very low; however a remarkable percentage of patients treated with EVE achieved some grade of tumor shrinkage, as reported in the waterfall plots.
Special Consideration: EVE ± SSA
Octreotide and lanreotide are the only two SSAs usable in clinical practice, also for non-functioning lung NETs. Pasireotide is just investigational.
Provided that in functioning NETs an SSA should be done for syndrome control an open debate remains about the EVE + SSA in non-functioning NETs.
The role of SSA in reducing the expression of insulin-like growth factors (IGF) and epidermal growth factor (EGF) along with EVE suggests the hypothesis that these two drugs work synergistically to arrest cell growth and to control hypersecretory activity in NETs.74 However, despite the strong biological rationale, there are no absolute clinical data to propose the combination of EVE and available SSAs in nonfunctioning lung NETs.
Although the LUNA study showed that EVE + PAS LAR was active and potential effective no practical conclusions can be drawn from that due to the type of study and unfortunately no further investigational plan exists to check the efficacy of this combo in lung NETs.
Special Consideration: EVE in Functioning Lung NETs
Although from the analysed studies a clinical impact of EVE + OCT LAR can be supposed also in functioning lung NETs EVE was approved just for non-functioning lung NETs due to the unmet statistical endpoint of the RADIANT-2 trial.
While EVE is utilized in NETs for tumor growth control, recent studies supported its use also for syndrome control in refractory functioning NETs.75,76
Furthermore it should be considered that in the LUNA trial 23% (n=28) functioning lung and thymus carcinoids were included. Similarly in the ITMO study 26% (n=13) functioning NETs were included and the first-line EVE+OCT LAR combo resulted active regardless of the presence or absence of carcinoid syndrome.
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