Radionuclide Theranostics in Neuroendocrine Neoplasms: An Update

NETTER-1 was a phase III randomized, multicentric, open-label trial which aimed to evaluate the safety and efficacy of PRRT in patients with progressive well-differentiated and SST-positive midgut NET. Progression-free survival (PFS) was longer in the 229 patients of the study arm (who received 4 cycles of 7.4 GBq of [177Lu]Lu-DOTATATE every 8 weeks and 30 mg octreotide LAR every 4 weeks) vs the control arm (FDA-approved off-label use of high-dose octreotide LAR every 4 weeks) [11]. The final results showed a longer median overall survival (OS), for the PRRT arm (48 months vs 36.3 months), although not statistically significant, due to a high rate of cross-over of the patients in the control arm [12••]. In a deeper analysis adjusting survival of those patients who crossed-over to PRRT (36%), the adjusted median OS was 30.9 months in the control group [12••]. The Netter 1 trial showed that PRRT is safe: final results showed that in the whole study, 7/111 (6%) patients had grade > 3 treatment-related toxicity, i.e., nephrotoxicity, grade > 3, 5%; hematological toxicity, 2%, myelodisplastic syndrome (MDS) [12••].

Gordon et al. recently published an analysis of their 5-year experience in administering [177Lu]Lu-DOTATATE after its approval. They treated 143 patients with advanced NET, administering ~ 8 GBq for 4 cycles every 8 weeks, and observed a median PFS of 32.3 months, a median OS of 72.5 months, and no evidence of renal toxicity, while MDS occurred in 5% of the subjects [13]. Favorable results were also reported in Brazilian (n = 36; mPFS = 23.0; OS = 30.0 months for G3 patients) [14], Polish (n = 167; mPFS = 29.3; OS = 34.0 months) [15], and Korean (n = 64; mPFS = 21.7; OS not reached within the 15.7-month follow-up) [16] cohorts.

PRRT was also reported to be safe in the elderly (Theiler et al. described a comparable safety profile in young and elderly patients aged > 79) [17] and in patients with chronic kidney disease [18].

In a large cohort of 1631 patients who received PRRT from 1999 to 2019, Chantadisai et al. reported therapy-related myeloid neoplasms (t-MN) in 30 cases only (1.8%), with a median latency period (from first PRRT to diagnosis of t-MN) of 43 months (range 6–123). The median OS from diagnosis of t-MN was 13 months (all patients), 6 months in the acute myeloid leukemia subgroup (seven patients), and 15 in the MDS subgroup (23 patients) [19].

Although PRRT was reported as a safe therapeutic option in NET patients with up to 50% liver involvement [20‐22], a more recent study by Gococo-Benore et al. investigated the risk of radiation-induced hepatotoxicity in patients with more than 75% of liver involved. Of 15 patients included (371 screened), only one experienced hyperbilirubinemia (grade 1 hepatotoxicity) and no one went through grade 3–5 hepatotoxicity, highlighting the potential feasibility of PRRT also in high-burden liver disease [23•].

Overall, the most recent studies confirm the knowledge acquired so far regarding PRRT safety and efficacy and show comparable outcome data, demonstrating that this therapeutic option is founded on solid evidence [9, 10].

Given the limited therapeutic options for progressive GEP-NEN and the known frequent adverse events caused by sunitinib and everolimus, retreatment with [177Lu]Lu-DOTATATE (R-PRRT) has been considered for NET patients who progressed after receiving first course PRRT (I-PRRT), with either [177Lu]Lu-DOTATATE or 90Y-PRRT. In a meta-analysis by Strosberg et al., including 13 studies investigating R-PRRT (comparable indications), a similar safety profile was observed in comparison with I-PRRT (grade 3–4 toxicity of any type in 5% of patients, hematologic toxicity of grade 3–5 in 9%). The estimated PFS was > 12 months in all the sub-groups, with a DCR (disease control rate) of 70%, but OS was not reported in all included studies [24]. OS data were available in the studies by Severi et al. (n = 26; median OS after retreatment = 36 months), Rudisile et al. (n = 35; median OS after I-PRRT not reached within a follow-up of 71 months, median OS after retreatment = 51 months), and Van Der Zwan et al. [25‐27]. Van Der Zwan et al. investigated the largest sample (n = 181) of retreated patients with bronchial or GEP-NET, receiving a single radiopharmaceutical ([177Lu]Lu-DOTATATE) and up to three treatment courses: patients were selected for re-(re)treatment if they had benefited from I-PRRT with a minimal PFS of 18 months. Patients received an additional cumulative dose of 14.8 GBq of [177Lu-DOTA,Tyr3]octreotate over two cycles per retreatment with R-PRRT or re-retreatment with PRRT (RR-PRRT). PFS was 19 months across all primaries. Combined OS after I-PRRT plus R-PRRT and RR-PRRT was 80.8 months (95% CI 66.0–95.6) [27].

Across studies investigating re-treatment, all courses consisted of 1 to 6 cycles and the doses administered were variable, but in 6/7 works where [177Lu]Lu-DOTATATE was employed for both I-PRRT and R-PRRT, they were superimposable, i.e., 7.4 GBq per-cycle [26‐29].

More recent studies confirmed the safety profile of R-PRRT and a PFS > 12 months: in a retrospective single-center study, Sitani et al. observed an acceptable safety profile (no grade 3–4 toxicity) and a PFS of 17 months after R-PRRT in a population of 22 re-treated patients, while the median OS was not reached during the follow-up period of 72 months [30•]. Silva et al. reported a median PFS of 17.5 months (IQR 7–39) for PRRT re-treated patients (n = 22), longer PFS after 2 cycles vs 1 and a median OS from I-PRRT of 66 months (IQR 65–90), without significant toxicity except for a lowering of platelet count (grade 1 toxicity, 10 patients, P-value = 0.055) [31].

Interestingly, Rodrigues et al., in addition to the outcome data of 40 patients treated with a second course of PRRT (PFS = 19.37; median OS = 122), analyzed the predictive value of [18F]FDG PET/CT status before and after the first and the second PRRT course. They found a more favorable outcome after the second PRRT course in the FDG-negative group (n = 26; median OS = 145.5 months; 95% CI 83.34–207.67) than the FDG-positive group (n = 14; median OS = 95.06 months; 95% CI 48.36–141.77) [32].

Across the different studies, the minimum PFS from the first PRRT, required as re-treatment eligibility criteria, was very heterogeneous, i.e., a PFS after the initial PRRT of > 12 months, ≥ 6 months, and no fixed time, respectively, in the works of Sitani et al., Silva et al., and Rodrigues et al. [30•, 31, 32]. Criteria for choosing a time-interval over another were not proposed in any of the studies.

Other limitations of the available works include the retrospective study designs, different treatment response criteria, and the heterogeneous populations in terms of initial treatment (radiopharmaceutical/doses/number of cycles), variability of time to progression (TTP), and intervening therapies from the first PRRT.

The multicenter randomized controlled trial ReLUTH, still recruiting, is the first prospective trial evaluating PRRT retreatment. It aims to compare two different [177Lu]Lu-DOTATATE schemes of retreatment (2 + 2 cycles vs 2 cycles) in patients with intestinal NET progressing after 12 months from the first PRRT course, expecting that four cycles will be more effective than two, with limited adverse impact on safety [33].

In conclusion, preliminary results are supporting PRRT retreatment as a feasible option in patients progressing after I-PRRT. R-PRRT is expected to be particularly effective in cases presenting a good response to I-PRRT, with a similar limited toxicity profile with respect to the first course. Randomized controlled trials are needed to directly compare the survival benefit of PRRT retreatment to other therapy lines like sunitinib or everolimus.

Providing adequate evaluation of PRRT response in patients with advanced NET remains an unsolved problem. Criteria used so far for response evaluation of solid tumors, i.e., Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) [34], mRECIST [35], or WHO [36], are based on dimensional changes and are suboptimal for NET distinctive slow-growing lesions. Moreover, patients with metastatic NET frequently do not display a morphological response to systemic therapies, including PRRT, that frequently results in disease stabilization [37]. It has been demonstrated that preventing disease progression, either through stabilization or obtaining remission (a concept referred to as “disease control rate” (DCR)), produces comparable outcomes in NET patients [38]. Although not optimal, morphology-based response criteria are currently used in clinical trials because they provide a standardized framework for objective assessments. Conventional imaging is routinely used in clinical practice to document progression and subsequently start further-line treatments in advanced NEN. Therefore, contrast enhanced computed tomography or magnetic resonance imaging remains irreplaceable as their spatial resolution allows for the detection of small dimensional changes that may be missed by PET.

On the other hand, PET functional imaging may detect even non-enlarged nodes or bone lesions (either millimetric or without corresponding morphological changes on CT) when presenting high SST expression. In addition, mere changes in tumor dimension may lead to equivocal interpretation. For example, a stable lesion may mask intralesional de-differentiation while a decrease in tumor volume after chemotherapy could subtend a cyto-reductive effect on the most aggressive components without a significant effect on SST-expressing cells. In addition, an initial increase in tumor volume may be related to inflammatory mechanisms (i.e., pseudoprogression), involving up to 10% of patients after PRRT [39].

For this reason, a complementary evaluation by conventional imaging and SST PET/CT, and, when necessary, [18F]-fluorodeoxyglucose ([18F]-FDG), has been suggested to evaluate both dimensional changes and functional phenotypes. Nevertheless, in the EANM Focus 3 meeting, consensus was not reached on the preferential imaging technique to assess PRRT response [40].

In a recent retrospective study, Zwirtz et al. compared Choi, RECIST, and SST-PET/CT criteria in 34 patients who received at least two PRRT cycles. EORTC [41] was the chosen model for somatostatin-based evaluation, named MORE and based on maximum standardized uptake value (SUVmax). The authors conceptualized a new parameter, ZP, defined as the product of SUVmean and Hounsfield Units (HU) of target lesions. PET/CT was performed at baseline and after every PRRT cycle (mean of 3.2 months). Patients progressing after the second PPRT cycle according to PET-based criteria (MORE and ZP) had a shorter survival compared to responders, but not statistically significant, and OS was not reached. The authors observed significant variability between all different criteria, uncovering the weakness of current evaluation systems and suggesting further investigations of PET-based parameters for response assessment [42•].

Molecular imaging allows to obtain functional information on whole tumor burden that is not achievable otherwise, i.e., tumor volume parameters, whose potential value for response assessment is under investigation and will be discussed in the next chapter.

In conclusion, the formulation of NET-specific response assessment criteria constitutes an ambitious challenge and an unmet need.

Since advanced-stage NEN frequently display inter-/intra-tumor heterogeneity, various combination therapies have been considered in addition to PRRT, to improve efficacy and target all components of the whole tumor burden.

As for all radiation treatments, the issues of radiosensitivity and radioresistance are worth of consideration. It is known that chemotherapy can work both with a direct cytotoxic effect and as a radiosensitizer, contrasting DNA repair and cell proliferation; this rationale led researchers to analyze the combination of various cytotoxic treatments with PRRT, obtaining promising results on the outcome and safety profile [75‐77].

Nicolini et al. selected 37 patients with G1–G3 GEP-NET, with high uptake on both SST and FDG PET/CT, to combine PRRT with oral capecitabine, administered in between PRRT cycles. They found a median PFS of 31.4 months, with median OS not reached during the follow-up period of 38 months. Grade 3 or 4 hematological toxicity affected 16.2% of patients, diarrhea occurred in 5.4%, and asthenia in 5.4% of them, showing an acceptable safety profile [78]. This study, as well as those previously conducted by Kong et al. [79] and by Kashyap et al. [80] (both on the combination of PRRT with 5-FU), highlights the potential benefit of combined chemo-PRRT in patients with advanced GEP NET presenting with SST and FDG-positive PET/CT. In all of the cited works, chemotherapy was administered as low dose, solely for a radiosensitizer scope, as first defined by van Essen et al. in their pilot study [81].

Conversely, Parghane et al. employed a full dose of capecitabine-temozolamide (CAPTEM) in a “sandwich” scheme, administering chemotherapy between two [177Lu]Lu-DOTATATE cycles in 38 patients with SST and FDG-avid metastatic NET, obtaining favorable response rates in terms of estimated PFS rate ( 72.5%) and OS rate (80.4%) at 36 months (median PFS and OS not reached at a median follow-up of 36 months) [82].

Two parallel phase II randomized trials are focusing on the CAPTEM-PRRT ([177Lu]Lu-DOTATATE) combination versus CAPTEM alone in the treatment of pNET and versus PRRT alone in midgut neuroendocrine tumors (NCT02358356).

An alternative radiosensitizer method consists in contrasting the DNA repair mechanisms acted by tumor cells in response to radiotherapy. With this aim, some researchers employed poli-ADP ribose polymerase (PARP) inhibitors in combination with PRRT. Available data come mostly from preclinical studies [83, 84], but ongoing clinical trials are currently evaluating the use of olaparib (NCT04086485, NCT05870423, NCT04375267) and talazoparib (NCT05053854) in combination with PRRT.

Another approach to maximize PRRT efficacy is to hinder the neovascularization that frequently characterizes advanced tumors (including NEN), which tends to obstacle drug delivery, due to the fragile and disorganized blood vessels produced under the abnormal stimulation of VEGF. Sunitinib is a multi tyrosin kinase inhibitor with an anti-proliferative and anti-angiogenic action, only approved for the treatment of advanced pancreatic NET on the basis of the SUNNET phase III trial [85]. Its use in combination to PRRT as a radiosensitizer has been successfully explored [86, 87] and a trial is in progress (NCT05687123). The Occlurandom trial is currently investigating safety and efficacy of [177Lu]Lu-DOTATATE vs Sunitinib in unresectable progressive well-differentiated neuroendocrine pancreatic tumor (NCT02230176).

The efficacy and safety of 177Lu-Edotreotide PRRT in comparison with everolimus have been investigated in the COMPETE trial, actually completed but with results no yet presented, with PFS as a primary endpoint (NCT03049189). The COMPOSE trial (NCT04919226) is comparing 177Lu-Edotreotide with Everolimus or chemotherapy (folfox or captem) and it is still recruiting.

The association between PRRT and immune-checkpoint inhibitor nivolumab is being assessed in a phase II single arm trial, evaluating preliminary safety and efficacy of the combination in G3 NET and NEC (still recruiting, NCT04525638). Another clinical trial aims to evaluate the combination of pembrolizumab plus liver-directed therapy or PRRT (NCT03457948).

Another strategy that is currently under investigation is the upregulation of SST, as the cytotoxicity of PRRT strictly depends on SST density on the surface of tumor cells. Chemotherapy [88] and everolimus [89] were reported to promote the expression of SST and cold SST analogs were hypothesized to act in a similar way [90]. In addition, novel epigenetic drugs demonstrated the ability to successfully upregulate SST expression in vitro [6] and in vivo [91], potentially enabling PRRT in cases of initial low SST expression. Modulating SST is desirable to strengthen the therapeutic effect of PRRT, but the optimal approach to increase SST expression is not defined yet.

Lastly, the benefit of dual-PRRT, i.e., the combination of different PRRT pharmaceuticals, has been outlined by different studies [92, 93], and it is worthy of consideration for future trials.

The therapeutic options available to date for advanced NEN can target different molecular pathways in the absence of clear prioritization or established sequencing protocols. The studies conducted so far suggest that a synergistic effect with PRRT may be expected but robust evidence is still needed.

The superiority of PRRT over cold somatostatin analogs as a second-line treatment for advanced G1 and G2 GEP-NET is well-accepted. Bringing PRRT forward to first line has been recently considered for metastatic higher-grade NET. Netter 2 study (NCT03972488) is a phase III trial that aims to evaluate the efficacy of first-line [177Lu]Lu-DOTATATE to treat advanced high-grade G2 and G3 (ki67 > 10%; < 55%) SST-expressing GEP-NET patients, comparing it to long-acting release octreotide (4 cycles of 7.4 GBq [177]Lu-DOTATATE vs 60 mg octreotide every 4 weeks). Preliminary results have recently been presented and showed a median PFS (95% confidence interval) of 8.5 months in the control arm and 22.8 months in the PRRT arm, the latter with limited toxicity (≤ 3 cases of grade 3–4 leukopenia, anemia, and thrombocytopenia and one case of MDS) [94••]. ESMO 2020 guidelines report that PRRT may be considered in patients with NET G3 [9]; however, patients need to be carefully selected and prospective trials are warranted to further establish which patients with NEN G3 might benefit most from PRRT. The above discussed NETTER-2 trial has recently been initiated to address this issue (NCT03972488). Preliminary data on PRRT in NEN G3 (n = 280pts in four retrospective studies) [95‐98] reported disease control rates between 30 and 80% (PFS 9–23 months and OS 19–53 months).

Induction PRRT has been explored for unresectable tumors prior to surgery (i.e., neoadjuvant treatment) [99, 100] or followed by further maintenance cycles [101].

Minczeles et al. administered [177Lu]Lu-DOTATATE with the scope of downstaging in 49 patients with pancreatic NET. Of these, 26 underwent surgery with curative intent, obtaining a median OS of 14.7 years (95% CI 5.9–23.6), compared to 5.5 years (95% CI 4.5–6.5) for the PRRT-only group (P = 0.003). Median PFS was 5.3 years (95% CI 2.4–8.1) for the PRRT + surgery group and 3.0 years (95% CI 1.6–4.4) for the PRRT-only group (P = 0.02) [99].

A prospective on-going phase II single-arm trial (Neo.Lu.Pa.NET) aims to investigate evaluated safety and efficacy of neoadjuvant PRRT with [177Lu]Lu-DOTATATE followed by surgery for resectable pancreatic neuroendocrine tumors (NCT04385992).

Fluorine-labeled somatostatin (SST) agonists have been proposed as an alternative to [68 Ga]-labeled PET tracers due to the advantages of [18F] in terms of longer half-life (110 min vs. 68 min), easier distribution to other centers, more favorable positron range (resulting in better image quality), higher activity amounts available per center (in contrast with the limited [68 Ga] doses obtainable per single elution). In a recent multicenter study, [18F]F-Alf-NOTA-octreotide showed an equal or superior [68 Ga]Ga-DOTATATE/NOC detection rate (91.1% vs. 75.3%; P < 10–5) [102], and the first clinical studies on [18F]F-SiFAlinTATE described favorable tumor-to-liver and tumor-to-spleen ratios [103].

SST antagonists display pharmacokinetic characteristics (low internalization, reduced dissociation, higher receptor binding) and low backgrounds that translate into superior detection rates compared to SST-agonists. A recent bi-center prospective study compared [68 Ga]Ga-NODAGA-JR11 and [68 Ga]Ga-DOTATATE in a cohort of 100 patients with unresectable or metastatic NET. Superior detection ability and superimposable lesion uptake were found for [68 Ga]Ga-NODAGA-JR11 compared to [68 Ga]Ga-DOTATATE, with the latter being superior only in detecting bone lesions (but without statistical significance and justified by the lower JR11 bone marrow uptake). Sensitivity was higher for [68 Ga]Ga-NODAGA-JR11 (91.7%, range, 87.6–95.7%) compared to [68 Ga]Ga-DOTATATE (77.2%, range, 71.0–83.4%), using conventional imaging as a reference [104]. [177Lu]Lu-DOTA-JR11, the corresponding therapeutic radionuclide, has been shown to cause more hematologic adverse events than [177Lu]Lu-DOTATATE. Reidy-Lagunes et al. have hypothesized that 177Lu-DOTA-JR11 could target SST expressed by stem cells or progenitor cells [105].

[68 Ga]Ga-NODAGA-LM3 and [68 Ga]Ga-DOTA-LM3 are novel antagonists with similar high tumor accumulation [106]. In a newly published paper, Liu et al. described the use of four types of antagonists ([68 Ga]Ga-NODAGA-LM3, [68 Ga]Ga-DOTA-LM3, [68 Ga]Ga-NODAGA-JR11, and [68 Ga]Ga-DOTA-JR11) in 549 patients, with 181 of them having a [68 Ga]Ga-DOTATATE PET/CT scan as comparison. The authors found that only [68 Ga]Ga-NODAGA-LM3 produced a significantly higher uptake than [68 Ga]Ga-DOTATATE in the hottest lesions (SUVmax = 57.4 ± 38.5 vs. 40.0 ± 22.8, P < 0.001), while the other antagonists showed comparable or lower SUVmax then [68 Ga]Ga-DOTATATE. All the antagonists displayed a higher TLR compared to [68 Ga]Ga-DOTATATE [107].

SST-targeting tracers labeled with alpha emitters [212Pb], [213Bi] [108], and [225Ac] [109] have been developed for their promising characteristics, i.e., higher linear energy transfer and lower tissue penetration (40–100 µm) compared to beta-emitters, allowing to deliver higher cytotoxic radiation to the tumor while sparing normal tissues.

[212Pb]Pb-DOTAM-TATE was well tolerated in phase I studies [110] and it is currently under evaluation for treatment-naïve NET patients (NCT03466216).

An interesting and emerging setting is the possbility to use alpha emitters for PRRT to treat relapsing patients after 177Lu-PRRT failure. The use of [225Ac]Ac-DOTATATE has been proposed for 177Lu-PRRT refractory patients or patients with PD after the first 177Lu-PRRT course: Ballal et al. administered [225Ac]Ac-DOTATATE in 91 patients with metastatic GEP-NET, 57 of them with prior [177Lu]Lu-DOTATATE treatment. Median OS and PFS were not reached during the 24-month follow-up. Two of 79 patients (2.5%) had CR, 38 (48%) had a PR, and 23 (29%) had SD. The treatment was safe, without higher grade toxicities [111]. The on-going trial ACTION-1 is also investigating the feasibility of [225Ac]Ac-DOTATATE following PRRT with [177Lu]Lu-labeled-PRRT failure (NCT05477576).

Neuroendocrine liver metastases can be targeted with transcatheter intra-arterial liver-directed therapies, if surgery is not feasible.

Loco-regional treatments include embolization, chemoembolization, and radioembolization with [90Y]-glass/resin microspheres (preceded by [99mTc]-macroaggregates of albumin SPECT/CT for pre-treatment evaluation) or radioembolization with [166Ho]-microspheres (made of poly-l-lactic acid) [112]. Radioembolization with [166Ho]-microspheres presents the theranostic advantage of using a scout dose of [166Ho]-microspheres to safely evaluate their intra-arterial distribution before [166Ho]-microsphere treatment.

Intra-arterial (IA) PRRT has been proposed for NET patients with predominant liver involvement, hypothesizing a more favorable tumor uptake compared to the intra-venous (IV) administration of [177Lu]Lu-DOTATATE, thanks to the first-pass effect. Promising results were obtained through the comparison of IA and IV PRRT in different patient populations, with the limitations of the heterogeneous primary sites, SST expression, ki67, and previous therapies [113]. The LUTIA randomized controlled trial, conversely, was designed using an intra-patient control, injecting [177Lu]Lu-DOTATATE (4 cycles of 7.4 Gbq) in only one hepatic lobe, in 27 patients with bilobar NET liver metastases (G1 and G2 GEP-NET). The authors did not find significant differences between the tumor-to-non-tumor (T/N) uptake ratio of the two lobes on the 24 h post-treatment [177Lu]Lu-SPECT/CT after the first cycle, which was the primary endpoint (T/N IA = 17.4 vs. T/N control = 16.2; P = 0.299) [114]. Future trials are needed to evaluate this treatment strategy.

With respect to scheme personalization, Garske-Román et al. investigated a dosimetry-guided approach to allow the prolonging of PRRT cycles in patients that do not reach the limiting absorbed doses of 23 Gy to the kidneys or 2 Gy to the bone marrow within the standard 4 cycles of 7.4 GBq of [177Lu]Lu-DOTATATE each. They continued administering further cycles besides the first four in 200 patients, until achieving therapy-limiting doses. Results displayed that the individualized approach is feasible, with the limiting absorbed dose to the kidneys reached in 3 to 9 cycles in 123 patients and none experimenting the limiting dose to the bone marrow. Hematological toxicity regarded three patients (1.5%) with post-PRRT acute leukemia, and 30 (15%) grade 3 or 4 bone marrow toxicity. Eight patients (4%) had grade 2 kidney toxicity and one patient (0.5%) grade 4 kidney toxicity [115].

The value of personalized versus fixed schemes is under investigation (NCT03454763, NCT04917484).