A Multicenter Study Evaluating Efficacy and Safety of 177Lu-DOTA-TATE Based on Kidney-Dosimetry in Patients With Disseminated Neuroendocrine Tumors

Inclusion criteria

Step 1:

• ECOG 0-2
• Histologically verified neuroendocrine tumors with a Ki67 of at least 20 % or at least 20 mitoses/high power fields. If the tissue on which this determination is based is several years old, the investigator should consider the option of acquiring a new determination, especially if the behaviour of the tumor has changed since diagnosis
• Metastatic disease where complete resection is not considered possible or feasible
• Measurable disease
• Radiological disease progression during the last 14 months
• The largest metastases should have an uptake of 111In-octreotide that is greater than the uptake in the liver by planar scintigraphy. Metastases that are small, or located centrally, can be evaluated by SPECT to enable a correct estimation of the relative uptake. The majority of the tumor burden must demonstrate an increased uptake for lutetium-treatment to be considered
• Stable dose of somatostatin analogue for the past 3 months
• Estimated survival more than 6 months
• ANC more than 1.5 x 10 9/L
• Bilirubin less than 1.5 x upper limit of normal
• GFR more than 50 ml/min.
• Signed written informed concent

Step 2:

• Continues to fulfill all of the inclusion criteria, and none of the exclusion criteria, from step 1
• A maintained GFR (less than 40 % decrease compared to baseline AND GFR more than 50 ml/min)
• The treatment in step 1 have been administered with a maximal interval of 12 weeks
• Age under 70 years

Exclusion criteria

Step 1:

• Performance Status ECOG 3-4
• Proliferation index (Ki67) more than 20 % or more than 20 mitoses/hpf
• Loco-regional treatment during the last 3 months involving all of the measurable lesions
• Chemotherapy during the last 3 months, or longer if persisting toxicity exists. Earlier treatment with mTORi or TKI is permitted
• Other concommitant nephrotoxic treatment
• Modifications of the somatostatine dose in the last 3 months
• Serious heart disease
• Previous radiotherapy including more than 25 % of active bone marrow volume
• Pregnancy and lactation
• Extensive liver metastases (more than 50 % of liver volume)
• Symptomatic CNS metastases requiring corticosteroid treatment
• Ongoing treatment with interferon. This treatment should be suspended a minimum of 4 weeks before treatment with 177Lu-DOTA-TATE, or longer if there is persisting signs of toxicity
• Patients who have another metastatic tumor diagnosis

Step 2:

• Progressive disease since start of study treatment
• Organ toxicity grade 3-4 during step 1
• Serious hematological toxicity during previous treatment cycles (ANC less than 0.5 x 10 9 or platelets less than 50.0 x 10 9)
• Longstanding diabetes (more than 8 years). Patients with a well-controlled diabetes with a history of less than 8 years and a blood pressure less than 130/80 and no albuminuria (albumin/creatinine index)can be included
• Hypertension, i.e. more than 160/90 (for diabetics more than 130/80). Antihypertensive pharmacological treatment is permitted as long as there is no manifest albuminuria
• Previous liver embolisation
• Previous chemotherapy