Twenty-four studies were included in the review (1,791 patients, range 30 to 504): 16 PRRT studies (1,179 patients) and eight I-MIBG studies (612 patients); 22 studies were prospective. The authors reported that the overall study quality ratings ranged from poor to moderate. Twenty-two studies clearly recorded treatment doses and schemas of radionuclide therapy, one reported blinding, 18 had sufficient follow-up time and 23 analysed 80% or more of the patients for at least one clinical outcome. The authors reported that a detailed table of study quality results was available on request but this could not be obtained.
Six PRRT studies reported median overall survival time, which ranged from 16 months for patients treated with Y-DOTATOC to 46 months for patients treated with Lu-DOTATATE. Median survival time was 15 months for patients who had received a second treatment of Lu-DOTATATE following progression of their disease.
In one study (31 patients) no statistically significant difference was found between intervention (treated with In-DTPAOC or I-MIBG) and control (no treatment) groups for progression-free and overall survival rates. Three studies reported that patients with a complete response, partial response or stable disease after PRRT had a longer overall survival time than patients with progressive disease.
For I-MIBG studies median survival rates among stage III-IV neuroblastoma patients (median age of two to 6.6 years; three studies) were 49% at year one and 29% at year two for one study. An earlier study by the same authors demonstrated an overall median survival rate of six months with patients of the same condition and a similar age. One study demonstrated no statistically significant difference in overall survival rate at five years between intervention (I-MIBG treatment) (63%, 95% CI 47% to 75%) and control (no treatment) groups (47%, 95% CI 34% to 59%) for patients with progressive stage IV midgut carcinoid (p=0.10).
One study demonstrated that progression-free survival rates at five years ranged from 40% (95% CI 24% to 56%) with stage IV patients to 92% (95% CI 78% to 100%) with stage III neuroblastoma patients.
Response on imaging:
Comparison of PRRT studies was difficult due to different criteria being used for evaluation of tumour response and different definitions for partial response, stable disease and progressive disease.
For In-DTPAOC (two studies) the overall response rates were 5% (95% CI 0% to 15%) and 18% (95% CI 6% to 30%) for patients with various progressive stage III-IV neuroendocrine tumours.
For Y-DOTATOC (six studies) overall response rates ranged from 4% (95% CI 0% to 8%) with various progressive stage IV carcinoid patients to 28% (95% CI 19% to 37%) for patients with various mixed-status stage III-IV neuroendocrine tumours.
For Y-DOTALAN (one study) the overall response rate for carcinoid patients was 18% (95% CI 5% to 31%).
For Y-DOTATATE (two studies) overall response rates were 44% (95% CI 27% to 61%) for patients with various stage IV neuroendocrine tumours and 23% (95% CI 12% to 34%) for patients with various stage IV gastroenteropancreatic neuroendocrine tumours.
For Lu-DOTATATE (two studies) overall response rates ranged from 24% (95% CI 9% to 39%) for patients with various stage IV gastroenteropancreatic neuroendocrine tumours to 75% (95% CI 51% to 100%) for gastrinoma patients.
Six of the eight I-MIBG studies assessed tumour response on imaging; different criteria were used across the studies. Overall response rate ranged from 26% (95% CI 13% to 39%) for patients with various stage III-IV neuroendocrine tumours to 75% (95% CI 62% to 88%) with stage III-IV neuroblastoma patients.
Quality of life: Quality of life improved for some patients in all seven of the PRRT studies that assessed it; comparisons between studies and different therapeutic radiopharmaceuticals could not be made due to clinical differences. No quality of life assessments were reported in any of the I-MIBG studies.
For PRRT studies, severe toxicities included: development of myelodysplastic syndrome (MDS) and/or leukaemia (8% in one study) with In-DTPAOC; grade 4 renal toxicity (0.9% to 3.4% across three studies) and MDS (2% in one study) with Y-DOTATOC; and grade 2 renal toxicity (30% in one study), renal insufficiency (0.4% in one study), hepatic insufficiency (0.6% in one study) and MDS (0.8% in one study) for Lu-DOTATATE. Studies that investigated the efficacy of Y-DOTATOC, Y-DOTATATE and Lu-DOTATATE infused lysine and arginine amino acid solution to protect patients' kidney function.
For I-MIBG studies, severe toxicities included: bone marrow replacement; primary or secondary leukaemia; MDS; leukaemia; secondary malignancies (among three to five year old children with stage III-IV neuroblastoma); and death. Proportions of patients who developed these conditions ranged from 0.3% to 43% (results from individual studies are reported in the paper).
Further results from all of the outcomes were reported fully in the paper.