1 Introduction
Over the past 2 decades, peptide receptor radionuclide therapy (PRRT), has been proved to be an effective and safe therapeutic option in patients with inoperable or metastatic well-differentiated neuroendocrine tumors (NETs) [
8,
32,
34,
40,
41,
46]
.
Somatostatin receptor ligand (SrL) labelled with Indium-111 (
111In-DTPA-Octreotide) was the first radiopharmaceutical applied with encouraging results in terms of symptomatology. Nevertheless, objective responses were rare, while hematological side effects were also observed [
40]. Subsequently, new analogues labelled with the β-emitting radionuclides Lutetium-177 and Yttrium-90 were introduced. In the following 15 years, uncontrolled trials on both radiopharmaceuticals in different types of NETs reported disease-control rates (DCR)s of 68–94% and a significant increase of overall survival (OS) and progression free survival (PFS) ([
8,
13,
34], Kwekkeboom et al. 2005)
. Furthermore, biochemical and symptomatic responses, and quality of life improvement have been reported [
36].
Data about safety of PRRT are comforting. The most frequent acute side effects are nausea and vomiting, fatigue, abdominal pain and myelosuppression, that are generally mild, self-limiting and reversible. Carcinoid crisis is very rare. Kidney damage is a long-term side effect, but renal failure can be prevented by the coadministration of positively charged amino acids. Haematological toxicity, such as leukemia or myelodysplastic syndromes has been reported in less than 5% of patients who received PRRT [
47].
Despite this long-time experience, for many years data about efficacy and safety of PRRT derived only from few early-phase trials or retrospective studies, until the publication of the recent first randomized phase III NETTER-1 trial [
74]
, comparing PRRT (
177Lu-DOTATATE) to high-dose octreotide LAR in patients with progressive inoperable or metastatic midgut NETs. The objective response rate (ORR) was 18% in the
177Lu-DOTATATE group versus 3% in the control group (
p < 0.001). The median progression-free survival (mPFS) was not reached in the
177Lu-DOTATATE group and it was 8.4 months in the control group (hazard ratio for disease progression or death with
177Lu-DOTATATE vs. control, 0.21; 95% CI, 0.13 to 0.33;
p < 0.001), which represented a 79% lower risk of disease progression or death in the
177Lu-DOTATATE group than in the control group. In addition, the interim analysis indicated that the estimated risk of death was 60% lower in the
177Lu-DOTATE group than in the control group (hazard ratio 0.40;
P = 0.004). These impressive results, seen in the NETTER-1 study, substantiates the use of PRRT in NET patients.
However, no sequence is as yet standardized by major international guidelines and the correct positioning of PRRT in the therapeutic algorithm is up for discussion.
The antitumor effect of PRRT is based on the radiolabeled SrL ability to bind somatostatin receptors (SSTR), highly expressed in NETs [
39]. A strong expression of SSTR-2 (Krenning Scale 3–4 as fulfilled in the NETTER-1 trial) seems to have an impact on the outcome, but also site of the primary tumor, tumor load, grading and the Positron Emission Tomography (PET) with
68Ga-DOTA-peptide and/or with
18F-fluorodeoxyglucose (18F-FDG) uptake may influence the efficacy of PRRT. Some prospective and retrospective studies analyzed these parameters individually, while the potential role in predicting response to PRRT of these factors has never been explored globally. Moreover, according to a recent experience of [
9], high predictive and prognostic power on the outcome with PRRT, are observed for the “NETest”, a specific liquid biopsy which measures neuroendocrine tumor gene expression in blood and aims at defining the biological activity of an individual NET in real time. The achievement reported in the cited paper are promising, also regarding the prediction of response to PRRT in different types of NET.
Nevertheless, since the NETest is not widely available in clinical practice, and it has still to be tested and further validated in other studies, the identification of reliable predictors of tumor response to PRRT is still urgently needed, to improve the outcome of PRRT, providing directions in clinical decision-making, toward a more personalized therapy.
The aim of this review is to revise all potential predicting factors of response to PRRT, finally defining the perfect identity of the eligible patient who can benefit most from this therapy.
4 The NETest
The parameters so far described to predict tumor response and patient survival are all based on radiological, istological or nuclear evidences; different from that, the “NETest” consists of a liquid biopsy, evaluating in real time the transcriptional tumor profile (or its “gene signature”) by blood sample. The NETest aims at defining the neoplasm precise biological activity, including diagnostic accuracy, prognostic value, and predictive therapeutic assessment.
The push for the development of such test are to be found in some of the limitations of most prognostic and predictive factors for NENs evaluation, such as low reproducibility and high inter-variability. The diagnostic accuracy of this mRNA-based evaluation seems to be able to identify all NEN types, including small non metastatic tumors.
Regarding the predictive efficacy of the NETest prior to PRRT, an algorithm that integrates specific gene transcripts with tissue Ki67 values (either from primary or metastasis) was developed by the authors to generate a PRRT Predictive Quotient (PPQ) characterized by two prediction outputs: “PRRT-responder” or “PRRT-non-responder”. The authors developed and validated the PPQ in three prospective studies, enrolling a total of 158
177LU-PRRT treated patients: in these different cohorts, fifty-one marker genes were measured to best predict PRRT efficacy and it was observed that PPQ correlated accurately with PRRT both in responders (97%) and in non-responders (91%); even changes in gene expression reflected in treatment response assessment scored with RECIST. Conversely, no gene signature is available at the moment for the assessment of the risk for mielo- or nephrotoxicity in PRRT [
10]. They conclude that the NETest showed results thus far unmatched by other commonly used markers.
The impressive results showed in the paper by [
10] are undoubtedly promising, still, yet to be confirmed in other studies, which are certainly eagerly needed, in order to further assess the value and accuracy of NETest in diagnosing and predicting outcome in patients with NETs.
5 Discussion
PRRT is now a well defined therapeutic option to treat GEP NET patients after failure of SSA, while predictors of tumor response to PRRT and patient survival after treatment has not yet been found.
The present study tried to define the identikit of the “perfect patient” to candidate to PRRT. However, to distinguish between predictors of response factors and prognostic factors is challenging. The inhomogeneous distribution of primaries, small sample size of the studies and different outcomes taken into consideration, together with the different follow up and timing of evaluation, may have hampered the chance to identify which patients may benefit from PRRT more than others in terms of survival or tumor response.
Regarding
primary origin, GEP NET seem to be more responsive than non-GEP NET, both in terms of ORR [
4] than PFS [
4,
5], while among the GEP tumors, panNET show a better ORR than small intestinal NET[
60].
If the studies reporting primary site to be a predictor factor of response to PRRT are few, little more are the ones showing absence of any correlation between primary tumor and ORR [
17,
59,
68,
70,
78,
79]. The reported evidence that panNET respond better than small intestinal NET, but without any significant difference in PFS, is likely to correlate to the known phenomenon of shorter PFS of patients with panNET despite a more pronounced initial response to PRRT in terms of ORR [
44,
46]. In the setting of NEN with unknown primary, PRRT is a potentially effective therapeutic option, although there are not univocal data in literature [
3].
Although also concerning
tumor burden (TB) no concordant conclusions can be drawn, most of these studies ([
18,
23,
24,
46] e [
43,
77,
82], [
49], Kolasinska-Cwilla et al. ) reported, in patients with low liver TB (<25% or < 50%, according to the different criteria considered to define the liver tumor load in each study), a statistically significant longer DFS after PRRT than in patients with a high liver TB (DFS range 21–49 months vs 8–28 months). Not only the presence of liver metastases, but also the overall tumor load, including other metastatic sites and even the primary tumor (if not resectable), should be taken into account when considering PRRT as appropriate choice for patients with advanced NETs. For instance, some evidences reported that patients with bone metastases had a higher risk of progression after PRRT than those without bone metastases [
46]. Similarly, the stage of disease seems to significantly affect the hazard ratio for disease progression after PRRT [
14]. In summary, some evidences from retrospective studies suggest that patients with a low TB, especially in the liver, may benefit most from PRRT. Therefore, waiting for tumor progression before PRRT administration or choosing PRRT for patients with a large tumor load might be not appropriate. The TB must be included and carefully weighed in the multidisciplinary discussion of the individual patient for the indication to PRRT.
Somatostatin receptor imaging is a mandatory prerequisite for the use of PRRT. First studies were based on Somatostatin Receptor Scintigraphy (SRS) with 111In-pentetreotide (Octreoscan) but, in recent years, 68Ga-DOTA-peptides PET/CT showed a better diagnostic performance than SRS. At now, 68Ga-PET represents the method of choice for the “in vivo” evaluation of SSTR expression, allowing also the calculation of semiquantitative parameters such as SUVmax and improving imaging resolution. At this purpose, the collection of further data with the larger number of PET scans performed today, will allow us to drawn conclusion in a comparative, retrospective analysis including the Octreoscan era. Among the papers analyzed, a half identified SUVmax as a predictor of response to therapy, whereas the remaining half either did not find significance or identified other parameters able to predict outcome of PRRT treatment. Three studies identified a SUVmax cut-off to select patients for PRRT, but to establish the potential ability to predict response to PRRT further studies are needed. In conclusion, Gallium uptake is an inclusion criterion for PRRT, but poorly correlates with response to therapy and it is not a predictive factor in an individual patient. This confirms that the expression of sstr is not the unique determinant of efficacy of PRRT [
24].
On the contrary,
18F-FDG PET seems to have a role in predicting disease progression, tumor response and survival in patients with advanced NETs, treated with PRRT. Most studies suggest that the patients with negative baseline scan may benefit from PRRT more than positive patients, also showing that a high 18F-FDG SUV
max is associated with a poor outcome to PRRT and with disease progression [
51‐
53,
75]. Similar results also emerged in 22 patients with pulmonary NET, evaluated retrospectively [
58]. Therefore,
18F-FDG PET must be taken into account during therapeutic decision-making and multidisciplinary assessment of different patients.
The most interesting and promising criterion to predict response to PRRT seems to be
ki67 index. Although in general the ki67 index is being recognized as a powerful determinant of survival in patients with GEP NETs and it is known as a major prognostic factor for NETs [
56,
57,
65], its relevance in metastatic disease and potential cutoff values for the different treatment modalities are still undefined because of a lack of data. Keeping this concept in mind, nevertheless we have found many evidences in the literature that attribute to the degree a predictive value of response (ORR) or survival (PFS) after PRRT [
1,
5,
9,
14,
15,
19,
21,
23,
24,
32,
35,
52,
59,
61].
ki67 index proved to be the strongest predictor of outcome in that patient cohort [
24]. Authors reported that, even though G2 tumors with a ki67 index >10% respond in a similar manner to lesions with ki67 < 10% (accordingly to their previous results above stated), G2 NENs with ki67 > 10% show earlier progression after PRRT (median PFS of 19 vs 31 months). Although it is well known that grade affect prognoses of NENs in general, this evidence shows that grade provides prognostic stratification in a uniformly treated cohort of PRRT pretreated patients.
Moreover, [
14] confirmed the role of grade as crucial therapeutic prognostic factors for response to PRRT in NETs. In fact, grade was a risk factor for PD at multivariate analysis (NET G2 vs NET G1, HR 3.481,
p = 0.003). Similar findings were reported in another five recent studies [
1,
5,
15,
35], where different populations were analyzed and different Ki67 proliferation index thresholds used, but all found significance about longer survival associated with lower grade.
Again, the recent study by [
9] demonstrated that multiple regression analysis identified only grading as factors associated with PRRT outcome (p 0.004), a part from the new promising NET test.
Proliferation index calculated by ki67 labeling has some limitation that could influence part of these reported results. One of these limits is the intratumoral heterogeneity of ki67 index [
28]. Although it is well known that Ki67 may differ between primary lesion to synchronous or metachronous metastases and even between two different sites of metastases, [
28] in none, but one, of cited papers it is specified whether the pathology sample was harvested from the primary or metastatic lesions. The origin from surgical specimen or simple biopsy was reported only in the 25% of the considered report, as well. Anyway, despite such limitation and potentially confounding factors, evidence about the predictive role of grade on PRRT was found by most of the authors. In this respect, to overcome issues of temporal and spatial inaccuracy of ki67 index, an alternative tool such as a FDG PET could provide a whole imaging of the aggressiveness of tumor, with a picture of all metastatic sites together and at same time ([
7], Garin et al 2009).
However, we must to consider that other studies ([
22,
4960,
62,
82]
) in literature do not define grade as predictor of response after PRRT and one study reported some conflicting, but finally negative, results [
17]. Another limit of these conclusions about grade is that some authors in their papers consider grade cathegory (WHO 2010, G1, G2, G3 groups), while others consider different cut-off of ki67 such as 2%, 5%, 10% and 20%. A cut-off of ki67 has not been univocally identified.
Finally, we must consider that PRRT efficacy is affected by previous therapies and little evidence is available about the appropriate position of PRRT in the NET treatment sequence. In this respect it would have been of great interest to assess the response to PRRT based on the positioning of this therapy: in first, second line or further lines. However, of course, this data is not reported in all studies in a homogeneous way. Two of the wider and most recent case series have only partially analyzed the problem [
1,
5].
Baum et al., out of a study population of more than 1000 patients, showed a significant disadvantage in terms of OS in a subgroup of patients who had received PRRT after more than three previous lines, and who represented around 19% of the enrolled population. In contrast, statistically longer OS was recorded in the group of second-line PRRT-treated patients (28% of patients enrolled).
This data, however, can also be interpreted as a consequence of the fact that OS is a factor that reflects patient’s prognosis and it is evident that a patient, who has already performed more than 3 treatment lines, is later in his history natural disease. The outcome of these patients will be probably more influenced by their advanced stage than sequence of therapies received. In the series published in 2019 from Aalbersberg et al., while reporting the percentages of treatment naive patients, of those in the first, second or subsequent lines, then does not analyze the response based on treatment line. On the other hand, a lower effectiveness of PRRT when performed after chemotherapy or interferon is reported. The NETTER-1 trial [
74] demonstrated a lower risk of disease progression or death of 79%, in a setting of second line treatment, after failure of “cold” somatostatin analogues. For the future, further insight on sequence will be derived from the NETTER-2 trial, although it will be conduct on a different population (
clinicaltrials.gov).
Amongst future prospective, the recent study by [10] demonstrated that an algorithm including circulating NET transcripts and Ki67 proliferation index from primary or metastatic lesions correlated accurately with PRRT responders vs non responders and predicted PRRT efficacy. The gene signature that characterize the NETest showed promising and impressive results on discerning such patients, but not enough studies have confirmed these results so far and NETest, to date, is not routinely performed.
In conclusion, to date we have mostly prognostic (tumor burden, FDG uptake, grade) than predictive factors to predict efficacy for PRRT. The perfect patient, selected by Gallium DOTA-peptide PET uptake (or other somatostatin receptor imaging), will be likely characterized by a FDG PET negative scans, a relatively limited liver TB, a ki67 index <20% and will respond to PRRT irrespective to primary tumor origin. Nevertheless, at this moment the identikit of the perfect patient for PRRT therapy is a puzzle without some pieces. Still we cannot disregard a multidisciplinary discussion of the individual case to select the patients who will mostly benefit from the PRRT treatment.
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