European Nuclear Medicine Guide
Radiopharmaceutical: Lutetium-177 (177Lu-[DOTA0, Tyr3]) oxodotreotide or [177Lu]Lu-DOTA-TATE
Nuclide: Lutetium-177 is a medium-energy β-emitter with a maximum energy of 0.5 MeV, a maximal tissue penetration of 2 mm, and a half-life of 6.7 days. It also emits low-energy γ-rays at 208 and 113 keV with 10% and 6% abundance, respectively, allowing scintigraphy and subsequent dosimetry with the same therapeutic compound [47].
Activity: 7.4 GBq per cycle; four cycles every 8 weeks.
Administration: i.v.
[177Lu]Lu-DOTA-TATE is a radiolabelled somatostatin analogue ue developed for the treatment of patients with SSTR-positive neuroendocrine tumours (NETs). As such, [177Lu]Lu-DOTA-TATE is taken up by areas of increased sstr-2 density.
Eligibility and clinical decision-making should be based on multidisciplinary discussion. Eligibility criteria include:
Medical history report from the (referring) physician containing a summary of all previous treatments (surgery, radiofrequency ablation - RFA -, chemotherapy, radiotherapy, current medication, etc.).
NETs proven by histopathology (immunohistochemistry).
Tumour uptake on SSTR imaging ([68Ga]Ga-SSTR analogue ues PET or, if unavailable and in the presence of lesions of at least 1 cm, Octreoscan or Tektreotyd) should be at least as high as normal liver uptake. SSTR imaging should not be older than 6 months.
Adequate morphological imaging (e.g. computed tomography - CT - and/or magnetic resonance imaging - MRI), not older than 3 months, preferably less than 2 months.
Life expectancy of at least 9-12 months.
ECOG 0–2
Signed informed consent.
Adequate bone marrow, kidney and liver functions.
Pregnancy.
Lactation is a relative contraindication due to radiation exposure to the child. Breast uptake can be seen in the pre-treatment [68Ga]Ga-DOTA-SSTR analogue ues PET/CT study, and discontinuation is strongly advised for ≥2-3 months. Milk preservation is not an option.
Renal impairment (i.e., creatinine clearance <40 mL/min, measured in 24 h urine collection).
Impaired haematological function, i.e., haemoglobin (Hb) <5 mmol/L (8 g/dL); platelets <75x109/L; white blood cell count (WBC) <2x109/L.
Severe hepatic impairment, i.e., total bilirubin >3 times the upper limit of normal, or albumin <30 g/L with an increased prothrombin time.
Severe cardiac impairment (NYHA class III-IV)
Renal protection: because the kidneys are critical organs, positively charged amino acids such as L-lysine (lysine) and/or L-arginine (arginine) are co-infused to competitively inhibit the proximal tubular reabsorption of the radiopeptide and thereby reduce renal retention. Usually, a solution of 25 g of lysine and 25 g of arginine in 1 L normal saline is infused over 4-6 h, beginning 30-60 min before PRRT.
Adequate anti-emetic medication should be given before starting aminoacidic premedication.
Somatostatin analogue use should be spaced out in relation to SSTR therapy as they might interfere with receptor targeting. Long-acting somatostatin analogue use formulations should be planned 4 weeks before SSTR therapy, and syndromic patients should be switched to short-acting formulations up to 1 day before SSRT therapy. Somatostatin analogue use should be restarted a few hours after therapy.
SSRT therapy should be administered over 30 minutes and not as a bolus. Regardless of the method of administration (gravity or by use of infusion pump), appropriate radiation shielding and aseptic technique of radiopeptide preparation and administration should be used. Particular attention must be paid to the PRRT administration route (usually through a peripheral administration should be performed via a central catheter) to avoid extravasation.
Therapeutic interventions should be undertaken to treat functional syndrome effects or exacerbation (e.g. carcinoid syndrome/hypotension, hypoglycaemia, hypergastrinemia, hypertension, hypotension, WDHA syndrome, electrolyte imbalance).
The EC Directive 2013/59/Euratom states (article 56) that exposures of target volumes in nuclear medicine treatments shall be individually planned and their delivery appropriately verified. Indeed, SSTR therapy may be performed considering a maximum total absorbed dose to the kidneys and the bone marrow. While the maximum absorbed dose for kidneys is commonly set at limits used in external beam radiation therapy (EBRT, 23Gy), the threshold absorbed dose for late kidney toxicity for [177Lu]Lu-DOTA-TATE treatment is uncertain; also, the threshold absorbed dose for haematologic toxicity is set at 2 Gy for the cumulative absorbed dose (derived from 131I studies).
A recent study enrolled 15 patients and showed that a median administered activity of 63.8 GBq (range 52-96.6 GBq) administered in a median of 9 cycles (range 8-13 cycles) was well tolerated and led to a survival benefit in patients with recurrent NETs [147]. However, the optimal protocol and standardized dosimetry methods are not yet standardized but usually need 3-time point acquisitions (i.e., 3-4, 96-100 and 192 h after radionuclide injection) with SPECT/CT imaging, acquired through medium-energy general-purpose collimators (energy window centred at 208 keV) [3,4].
A more recent study showed that in GEP-NET patients (mainly G2) treated with 4 cycles of [177Lu]Lu-DOTA-TATE, tumour and normal organ dosimetry can predict survival and toxicities, influencing clinical management. Indeed, 35 dosimetric studies were performed assessing a total of 146 lesions, mostly hepatic (65%) and lymph nodal (25%). The toxicity analysis showed a correlation between the hematologic parameters’ reduction and the absorbed doses by the spleen or bone marrow, while the mean absorbed dose by the kidneys did not correlate with nephrotoxicity during the studied period. Also, the absorbed doses (AD) by tumours significantly decreased between cycles and was significantly associated with tumour volume variation 3 mo after treatment end (p < 0.001), representing a significant survival prognostic factor. Indeed, the median PFS was 39.4m [31.1m to not reached] in patients with a mean total AD>91.4 Gy, and 23.6 mo [13–38.2 m] in patients with a mean total AD<91.4 Gy. Patients with a min total AD>52.5Gy by lesions had a higher probability of PFS (HR, 0.34; 95% CI, 0.14–0.81; P = 0.01) and OS (HR, 0.23; 95% CI, 0.06–0.82; P = 0.01) [5].
Furthermore, a recent study assessed the dosimetry of a standard 4-cycle PRRT protocol with [177Lu]Lu-DOTATE in GEP-NET patients, showing that the predicted mean cumulative AD to kidneys and bone marrow were 19.4 (SD, 8.7) and 1.0Gy (SD, 0.8), respectively [48].
Nonetheless, although dosimetry can have a clinical benefit [6], it is not part of the standard protocol for SSTR therapy based on the safety results from the NETTER-1 study using [177Lu]Lu-Oxodotreotide at a fixed activity of 7.4 GBq each 8 weeks (4 cycles, with concomitant amino acid infusions to reduce renal uptake), with the eventuality to halve the activity in case of toxicity. Considering the promising results of dosimetric approaches [7, 8] It would be advisable to perform a standardized dosimetric approach (especially in "frail" patients) to collect more data, according to the European directive described above. Moreover, the dosimetric data can be useful if the patient will again receive SSTR therapy(re-treatment) which is actually only feasible in research studies. [7, 8]
Therapeutic options for NETs include surgery, somatostatin analogue use, chemotherapy, molecularly targeted agents, locoregional therapies, and PRRT. Surgery with curative intent should be performed whenever feasible. In selected cases and within a multidisciplinary approach, SSTR therapy may be beneficial as a neoadjuvant therapy to render a patient accessible to surgery; however, most neuroendocrine tumours have developed metastases by the time of diagnosis.
As most NETs overexpress somatostatin receptors, medical treatment in the form of somatostatin analogue use such as octreotide and lanreotide can be used for symptom relief, as well as for the antiproliferative effect on midgut NETs. Interferon-alpha can also be used to relieve symptoms. Local (chemo-)embolization and RFA can be used to control liver metastases. Symptomatic response rates of 60-95% and biochemical response rates of 50-90% are achieved, while radiological responses of 33-80% have been reported. Selective internal radiation therapy (SIRT) has recently been introduced, and in a single prospective study enrolling 34 patients the objective response rate was 50% [9].
Systemic chemotherapy is mainly effective in patients with poorly differentiated NETs, neuroendocrine carcinoma, or progressive NETs of the pancreas. However, in well-differentiated midgut NETs the response rates to chemotherapy are low (7-20%). For neuroendocrine carcinoma, chemotherapy usually includes cisplatin, etoposide irinotecan, 5-fluorouracil, or capecitabine and oxaliplatin. For pancreatic NETs, (a combination of) streptozotocin, 5-fluorouracil and/or doxorubicin can be considered.
The results of the randomized NETTER-1 phase III study of patients with sstr-positive midgut NETs showed that [177Lu]Lu-DOTA-TATE with 30 mg cold somatostatin led to markedly longer progression-free and overall survival and a significantly higher response rate relative to 60 mg cold somatostatin [10,11].
A clear correlation between tumour absorbed doses and the response to the treatment was reported in pancreatic NETs [12].
Molecular targeted therapies have been introduced recently, and progression-free survival compared to placebo in patients with pancreatic NETs were respectively 11.1 versus 5.5 months for sunitinib and 16.7 versus 9.7 months for everolimus.
A randomized phase III trial investigating first-line [177Lu]Lu-DOTA-TATE in patients with grade 2 and grade 3 (20% < Ki67 ≤ 55%) advanced GEP-NET (NETTER-2) recently compared the combination of [177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high-dose (60 mg) of long-acting octreotide. As a result, the median PFS of the PRRT arm was 22.8 m vs 8.5 m in the control group, with similar adverse events percentage. [13]
In the registrative study NETTER-1 [14], the most common G3/4 AE were vomiting, nausea, diarrhoea and abdominal pain, which were transient and occurred in ≤ 7%.
The absorbed dose to normal tissues has been estimated in several studies based on sequential quantitative imaging, blood sampling and in one case urine collection [4,15,16]. Kidneys and (more seldom) bone marrow were reported to be the dose-limiting organs [17,18]. In these studies, the main route of excretion was found to be via the kidneys. These studies also showed that absorbed doses delivered to kidneys vary by an order of magnitude, from 0.2-2.0 Gy/GBq.
Indeed, long-term follow-up analysis of the more relevant studies confirmed a low percentage of significant renal and haematological adverse events (<5%) [19, 45].
A rare (1%) but potentially fatal event in NET patients receiving PRRT are hormonal crises due to excessive release of bioactive substances, which typically occur during or within 2 days of treatment (skin rash, diarrhoea, bronchospasm, and hypertensive crisis). Carcinoid crises should be treated with a high dose of cold somatostatin analogue ue, intravenous fluids, corticosteroids, and correction of electrolyte disturbances in case of diarrhoea/vomiting [20].
In September 2017, the European Commission approved the marketing authorization of [177Lu]Lu-DOTA-TATE (Lutathera®) for the treatment of unresectable or metastatic, progressive, well-differentiated (G1 and G2), sstr-positive gastroenteropancreatic neuroendocrine tumours (GEP NETs) in adults. The product remains in an investigational phase for other indications.