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, and this allows scintigraphy and subsequent dosimetry with the same therapeutic compound
Activity: 7.4 GBq per cycle; four cycles every 8 weeks.
Administration: i.v.
[177Lu]Lu-DOTA-TATE is a radiolabelled somatostatin analogue developed for 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:
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. A solution of 25 g of lysine and 25 g of arginine in 1 L normal saline is infused over 4-6 h and beginning 30-60 min before PRRT.
Adequate anti-emetic medication should be given.
Somatostatin analogues should be discontinued prior to PRRT as they might interfere with receptor targeting. Long-acting somatostatin analogue formulations should be stopped 6 weeks before PRRT, and syndromic patients should be switched to short-acting formulations up to 1 day before PRRT. Somatostatin analogues should be restarted one day after therapy.
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 (watery diarrhoea, hypokalaemia, and achlorhydria), electrolyte imbalance).
Treatments may be performed prescribing a maximum total absorbed dose to the kidneys and the bone marrow. 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]. While the maximum absorbed dose for kidneys is commonly set at limits used in external beam radiation therapy (EBRT), the threshold dose for late kidney toxicity for [177Lu]Lu-DOTA-TATE treatment is uncertain. The threshold dose for haematologic toxicity is set at 2 Gy for the cumulative absorbed dose.
Even though the photon yield is relatively low, the high amount of activity administered makes quantitative imaging with Lutetium-177 possible. It has been demonstrated that gamma camera imaging is feasible, and that activity can be quantified to within 20% accuracy depending on the volume imaged. Medium energy general purpose collimators with the energy window centred at 208 keV are recommended [36,148].
Although dosimetry can have a clinical benefit, the optimal protocol and standardized dosimetry methods are not yet established. The absorbed dose limits for normal tissue and the desirable absorbed dose to the tumour still need to be determined.
A limited number of studies have investigated absorbed doses to measurable metastases using gamma camera imaging. In one study a range of absorbed doses were calculated from single photon emission computed tomography (SPECT/CT) imaging and reported between 10-340 Gy from a standard administration [149].
The first large clinical study using [177Lu]Lu-DOTA-TATE was reported in 2005 and used 4 cycles with a 6-10 week interval between [150]. Cycle dosages were 3.7 GBq (100 mCi) in seven patients, 5.6 GBq (150 mCi) in 16 patients, and 7.4 GBq (200 mCi) in the remaining 108 patients. No dose-limiting toxicity was observed, and the schedule is considered both safe and effective. According to recent Phase III clinical trial, the most frequently used treatment protocol is based on 4 therapy cycles, each with an activity of 7.4 GBq every 8 weeks and with concomitant infusion of amino acids to reduce renal uptake. However, protocols delivering cycles of 7.4 GBq, until a maximum prescribed absorbed dose to the kidneys and the bone marrow is reached, are also under investigation [151].
Therapeutic options for NETs include surgery, somatostatin analogues, interferon, 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, PRRT 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 analogues 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 RAF are used to control liver metastases. Symptomatic response rates of 60-95% and biochemical response rates of 50-90% are achieved. 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% [152].
Systemic chemotherapy is effective in some patients, especially those 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 (a combination) of 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-I phase III study of patients with sstr positive midgut NETs showed that [177Lu]Lu-DOTA-TATE led to markedly longer progression-free and overall survival and a significantly higher response rate relative to cold somatostatin [7].
A clear correlation between tumour absorbed doses and the response to the treatment was reported in pancreatic NETs [149].
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 [177Lu]Lu-DOTA-TATE in patients with grade 2 and grade 3 advanced GEP-NET (NETTER-2) is currently under way. It compares the combination of [177Lu]Lu-DOTA-TATE with long-acting octreotide to treatment with high dose (60 mg) long-acting octreotide.
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 [148,153,154]. Kidneys and (more seldom) bone marrow were reported to be the dose limiting organs [155,156]. 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.
Treatment related kidney toxicity has not been reported despite long term follow-up of patients receiving a kidney dose over 28 Gy. This indicates that 28 Gy might be a conservative dose limit [157].
[111In]-In-pentetroctreotide was the first PRRT with clinical efficacy. Partial remissions were rare with this agent, and leukaemia and myelodysplastic syndromes were found in patients who received high cumulative doses.
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.