Prospective observational study of 177Lu-DOTA-octreotate therapy in 200 patients with advanced metastasized neuroendocrine tumours (NETs): feasibility and impact of a dosimetry-guided study protocol on outcome and toxicity

Abstract

Purpose: Peptide receptor radionuclide therapy in patients with neuroendocrine tumours has yielded promising results. This prospective study investigated the feasibility of dosimetry of the kidneys and bone marrow during therapy and its impact on efficacy and outcome.

Methods: The study group comprised 200 consecutive patients with metastasized somatostatin receptor-positive neuroendocrine tumours progressing on standard therapy or not suitable for other therapeutic options. A treatment cycle consisted of 7.4 GBq ¹⁷⁷Lu-DOTA-octreotate with co-infusion of a mixed amino acid solution, and cycles were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy. The Ki-67 index was ≤2% in 47 patients (23.5%), 3-20% in 121 (60.5%) and >20% in 16 (8%).

Results: In 123 patients (61.5%) the absorbed dose to the kidneys reached 23 Gy with three to nine cycles during first-line therapy; in no patient was a dose to the bone marrow of 2 Gy reached. The best responses (according to RECIST 1.1) were a complete response (CR) in 1 patient (0.5%), a partial response (PR) in 47 (23.5%), stable disease (SD) in 135 (67.5%) and progressive disease (PD) in 7 (3.5%). Median progression-free survival was 27 months (95% CI 22-30 months) in all patients, 33 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 15 months in those in whom it did not. Median overall survival (OS) was 43 months (95% CI 39-53 months) in all patients, 54 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 25 months in those in whom it did not. Median OS was 60 months in patients with a best response of PR or CR, 42 months in those with SD and 16 months in those with PD. Three patients (1.5%) developed acute leukaemia, 1 patient (0.5%) chronic leukaemia (unconfirmed) and 30 patients (15%) grade 3 or 4 bone marrow toxicity. Eight patients (4%) developed grade 2 kidney toxicity and one patient (0.5%) grade 4 kidney toxicity.

Conclusions: Dosimetry-based therapy with ¹⁷⁷Lu-DOTA-octreotate is feasible. Patients in whom the absorbed dose to the kidneys reached 23 Gy had a longer OS than those in whom it did not. Patients with CR/PR had a longer OS than those with SD. Bone marrow dosimetry did not predict toxicity.

Keywords: 177Lu-DOTA-octreotate; Dosimetry; Neuroendocrine tumour; Outcome; PRRT; Toxicity.

Fig. 1

Patients with small intestinal NET (SI NET) show lower objective response rates according to RECIST 1.1 than patients with all other types of tumours (Non-SI NET). The proportions of patients in the respective groups with complete and partial responses (CR/PR), stable disease (SD) and progressive disease (PD) or data not available for radiological evaluation (NA) are indicated. Shaded areas Proportions of patients in whom the absorbed dose to the kidneys reached 23 Gy (numbers of patients are given in Table 4)

Fig. 2

Progression-free survival (PFS; a, c, e) and overall survival (OS; b, d, f) from the start of therapy with ¹⁷⁷Lu-DOTA-octreotate in relation to absorbed dose to the kidneys, best morphological response according to RECIST 1.1 and proliferation rate (Ki-67 index). a, b PFS (a) and OS (b) in 123 of 124 patients in whom the absorbed dose to the kidneys reached 23 Gy (blue line) and in 76 patients in whom it did not (red line); grey line combined data. c, d PFS (c) and OS (d) in relation to best response according to RECIST 1.1: progressive disease (PD, red line), median PFS 6 months (95% CI 3–9 months), median OS 15.5 months (95% CI 5–36 months); stable disease (SD, green line), median PFS 28 months (95% CI 21–31 months), OS 42 months (95% CI 34–51.5 months); partial response/complete response (PR&CR, blue line), median PFS 31 months (95% CI 23–35 months), OS 60 months (95% CI 43 months, upper limit not reached, NR). e, f PFS (e) and OS (f) in relation to proliferation rate (Ki-67 index): grade 1, Ki-67 index ≤2% (red line), PFS 33 months (95% CI 24–41 months), OS 48 months (95% CI 40 months, NR); grade 2, Ki-67 index 3–20% (green line), median PFS 23 months (95% CI 19–28 months), median OS 41 months (95% CI 32.5–60 months); grade 3, Ki-67 index >20% (blue line), median PFS 14 months (95% CI 10–21 months), median OS 31 months (95% CI 19–39 months)

Fig. 3

Progression-free survival (PFS, a) and overall survival (OS, b) in 154 patients who stopped therapy for reasons other than progression or clinical deterioration. In 114 patients in whom the absorbed dose to the kidneys reached 23 Gy, PFS was 34 months (95% CI 31–37 months) and OS was 60 months (95% CI 47 months, NR). In 39 of 40 patients in whom a dose of 23 Gy was not reached, PFS was 20 months (95% CI 16–28 months) and OS was 33 months (95% CI 29–48 months; p < 0.0001 for PFS, p = 0.0004 for OS); grey line combined data, red symbols patient died, blue symbols patient alive, triangles patient received salvage therapy

Fig. 4

Progression-free survival (PFS, a) and overall survival (OS, b) in all 50 patients who received exactly four cycles of ¹⁷⁷Lu-DOTA-octreotate. In 33 patients in whom the absorbed dose to the kidneys reached 23 Gy, PFS was 35 months (95% CI 23 months, NR) and OS was 60 months (95% CI 47 months, NR). In 17 patients in whom a dose of 23 Gy was not reached, PFS was 16 months (95% CI 9–18 months) and OS was 19 months (95% CI 15 months, NR; p = 0.0003 for PFS, p = 0.0006 for OS, log-rank test; grey line combined data, red symbols patient died, blue symbols patient alive, triangles patient received salvage therapy

Fig. 5

A 43-year-old female patient with VIPoma. a Cropped whole-body scans (WBS) obtained on day 1 after treatment with ¹⁷⁷Lu-DOTA-octreotate during initial treatment (cycles 1–5) and salvage therapy. Note the change in size and uptake intensity of the different tumours throughout therapy. Imaging at the time of salvage therapy after progression shows new uptake in the skeleton, but the total tumour burden is still lower than at the start of therapy. b Absorbed organ doses (in absolute values and in relation to administered activity) to the kidneys, liver parenchyma and spleen , and to three representative tumour lesions with homogeneous uptake, measured in the same area during each cycle of initial treatment and during salvage therapy. c Layout of the dosimetry programme (implemented on a Hermes platform, Nuclear Diagnostics International AB). The hair cross is positioned on the metastatic uptake in the liver, the small circle corresponds to a 4-cm³ volume of interest (VOI). For tumour and solid organ dosimetry, calculations of absorbed doses were based on volume concentrations in small VOIs drawn on SPECT/CT images at three time-points (24 h, 4 days and 7 days after infusion). In this patient, three SPECT/CT scans were acquired during cycles 1, 2 and 4 and cycle 1 of salvage therapy. For the other cycles, one SPECT/CT scan was acquired at 24 h and the absorbed dose was calculated assuming unchanged kinetics from the previous therapy

Fig. 6

Absorbed doses to the kidneys in the first cycle (a, b) and the last cycle in each patient (cycles 2 to 10; c, d) during initial treatment. Throughout therapy, doses could decrease or increase. Shaded bars indicate patients who received an absorbed dose of 3 to 4 Gy to their right kidney in the first cycle (a). In their last cycle, absorbed doses to the right kidney varied between 2 and 6 Gy (c). Dose distributions in the left kidneys of the same patients correspond to shaded areas in b and d