Evaluation of molecular, dosimetric and ultrastructural imaging in the management of neuroendocrine tumors with Peptide Receptor Radionuclide Therapy: results of a prospective, monocentric, non-controlled phase II study

SUMMARY

Neuroendocrine tumors are a heterogeneous group of tumors that derive from endocrine cells, spread throughout the whole body. NETs were once thought to be relatively rare, however, their incidence and prevalence have increased substantially over the past 30 years. The grown incidence is most likely due to the increased use of endoscopy and improved diagnosis with current estimates of annual incidence of 5/100 000. As NETs often display a slow growth combined with long survival rates, prevalence is relatively high (35/100000).

Gastroenteropancreatic (GEP) NET, bronchial carcinoids, medullary thyroid carcinomas and pheochromocytomas and paragangliomas belong to this group of tumors.  A major difference of neuroendocrine tumors and carcinomas with respect to most other tumors is the large clinical effect despite the small size of the tumor, due to the storage and release of peptides and biogenic amines. These effects can be quite different for the same tumor type, making these tumors very difficult to handle.

The treatment of NETs is typically multidisciplinary and should be individualized according to the tumor type, grade, stage, tumor burden and the presence of symptoms. Surgery is the primary treatment and will result in a curative treatment for the vast majority of patients with localized disease; in case of disseminated disease, interventional radiology and systemic treatments such as somatostatin analogues (SSA), interferon, chemotherapy, new targeted drugs and peptide receptor radionuclide therapy (PRRT) are indicated.

Many NETs have high cell surface expression of somatostatin receptors (SSR), specific G-protein coupled transmembrane receptors, enabling the therapeutic use of SSA. Further, the SSR serves as a target for diagnostic imaging tracers, which combine stabilized SSA with radionuclides such as indium-111 for conventional scintigraphy or gallium-68 for PET-imaging. SSR-imaging also enables selection of patients for PRRT. Hereby, similar SSA peptides are labeled with beta-, Auger- or alpha-emitters. After intravenous injection, these compounds are internalized in the tumor cell via the SSR and cause DNA damage through their particulate emission upon decay.

Favorable clinical results, with complete to partial responses in 10-30%, were already obtained with 1,4,7,10-tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic-acid (DOTA)-D-Phe1-Tyr3-octreotide (DOTATOC) labeled with yttrium-90, a high energy β-emitter, and with (DOTA)-D-Phe1-Tyr3-Thr8-octreotate (DOTATATE) labeled with lutetium-177, a β-γ-emitter.

A clear dose-response relationship has been demonstrated between the absorbed dose in the tumor and the reduction in tumor volume, therefore the aim of clinical PRRT is to deliver the maximal dose to the tumor while keeping the absorbed dose to normal tissues within acceptable limits. Deterioration of renal function is the activity-limiting toxicity in PRRT, in particular when 90Y-DOTATOC is used. The radiopeptide is reabsorbed in the proximal tubulus and retained in the interstitium, leading to kidney irradiation. The co-administration of positively charged amino acids (AA), such as L-lysine and/or L-arginine, that competitively inhibit the proximal tubular reabsorption of the radiopeptide by binding to the megalin receptor, results in a reduction of the renal dose ranging from 9 to 53%. Despite kidney protection, renal insufficiency may become clinically evident, sometimes years after radionuclide therapy, especially for 90Y-DOTATOC. In the largest series of patients treated with 90Y-DOTATOC (1109 patients), 9.2% of the treated patients experienced grade 4 or 5 permanent renal toxicity; therefore, PRRT-induced kidney toxicity remains an issue to be adressed.

We performed a prospective clinical phase-II monocentric trial, screening 71 patients and enrolling eventually 50 patients for PRRT. All had histologically proven, metastatic NET in case of progressive or recurrent disease after conventional treatment. The main inclusion criteria was sufficient SSR expression, as documented by scintigraphy with 68Ga-DOTATOC (tracer uptake > normal liver parenchyma), and a biological effective dose (BED) to the kidneys < 37Gy after minimum 3 cycles of 90Y-DOTATOC at 100% of activity, based on earlier published data. We performed dosimetry in every patient before starting PRRT using 111In-pentetreotide.

PRRT, with co-administration of AA, consisted of 4 cycles of 90Y-DOTATOC, using 1.85GBq/m²/cycle, every 8 weeks, up to an estimated kidney BED of 37Gy. Response on therapy was evaluated by the CT-part of the 68Ga-DOTATOC PET/CT at 40 weeks after the first treatment. Renal function was controlled by 51Cr-EDTA-clearance measurement at 18 and 30 weeks after PRRT.

This research project aimed firstly to improve the clinical implementation of PRRT with 90Y-DOTATOC, which was achieved as PRRT was started in 50 Belgian patients.

A second aim was the prevention of kidney toxicity with patient-specific dosimetry. A prospective dosimetry protocol, with co-administration of the same amino-acid solution as during PRRT and using a BED of 37Gy as a threshold for kidney toxicity based on published data, was developed for this study and was proven to be a good guide for safe 90Y-DOTATOC-PRRT as it prevented rapid deterioration of renal function and evolution to severe nephrotoxicity in 98% of the patients (49/50).

In most protocols, 90Y-DOTATOC-PRRT shows objective responses in ~ 30% and stable disease in ~ 50% of patients with median progression-free survival (PFS) of 30 months. More sensitive, functional imaging methods that would allow early evaluation of the effect of PRRT in NET patients would be very useful to optimize the logistics of this treatment and would allow avoiding side-effects in non-responding patients.

Therefore we performed imaging with68Ga-DOTATOC PET/CT and DW-MRI at baseline and 7 weeks after the first treatment cycle (=PRRT1), to evaluate their potential discriminatory value between responders and non-responders and hereby to investigate their additional value in the response assessment and outcome prediction.

Based on semi-quantitative data (SUVmax and SUVmax 7w – baseline) on pre-PRRT 68Ga-DOTATOC PET, we were able to distinguish a subgroup of patients with a good prognosis after PRRT. This information is of interest in the follow up of those patients. Using DW-MRI, we could identify a subgroup of patients with a clear unfavorable evolution after PRRT on an early time point during PRRT. After validation in an external cohort of patients, this finding could be used to change patients from PRRT to another treatment, sparing them from the toxicity and the cost of the other treatment-cycles.

In conclusion, due to this research project, we did not only implement PRRT in UZ Leuven, we build up important experience in performing PRRT en pre-therapeutic dosimetry.

We managed, along with the dosimetry protocol, to provide additional selection criteria for PRRT, based on pre- and early therapeutic functional imaging methods, in order to treat patients with minimal toxicity and best responses as possible.