All patients were treated between December 2006 and May 2016. A total of 58 radioembolization treatments in 44 patients with progressive NELM were included. Baseline characteristics are shown in Table 1. Most patients had diffuse liver metastases with 96% having more than 10 lesions and 93% classified as diffuse, type III pattern [12, 13]. At the time of analysis, 24/44 (54%) patients had died.
PRRT and Radioembolization Procedure Details
Of the 44 patients, one patient received meta-iodobenzylguanidine monotherapy (131I-MIBG; strictly speaking, the molecular target is the norepinephrine transporter, which is a catecholamine pump, and not a peptide receptor, but for the purpose of this study regarded as ‘PRRT’), three patients received 90Y-DOTATOC monotherapy, 31 patients received 177Lu-DOTATATE monotherapy, and nine patients received a combination of different therapeutic radiopharmaceuticals (Table 2). Median time to radioembolization from diagnosis was 4.6 years (range 1.3–12.9 years), and median time to radioembolization from last cycle of PRRT was 353 days (range 4 days–6.3 years). No extrahepatic depositions of 99mTc-MAA were found on SPECT/CT. Median net administered 90Y activity was 1.67 GBq (range 0.4–5.5 GBq), 97% calculated by the body surface area (BSA) method. Most procedures were whole liver treatments (32/58, 55%) (Table 3).
Imaging and Clinical Response
An objective response rate of 16% and disease control rate of 91% were observed at 3 months according to RECIST 1.1 (CR 2%, PR 14%, stable disease 75% and progressive disease 9%). Malignancy-related symptoms were present at treatment in 23/58 (40%) of procedures prior to radioembolization. Abdominal pain (35%) and flushing (30%) were most frequently reported. Clinical response occurred in 15/23 (65%) of these patients after 3 months, with 7/23 (30%) having improvement of pre-treatment complaints and 8/23 (35%) experiencing complete resolution of pre-treatment symptoms after radioembolization. 8/23 (35%) remained symptomatic after radioembolization.
At 3 months after radioembolization, no clinical toxicities occurred in 37/58 (64%), known radioembolization-related adverse events occurred in 15/58 (26%), mainly transient abdominal discomfort, and the treating physician did not register clinical toxicities in 6/58 (10%; missing data or death). At baseline, most patients already had a variety of biochemical toxicities according to CTCAE v4.03 (Table 4). The most common newly developed CTCAE grade 3–4 biochemical and haematological toxicities were γ-glutamyl transpeptidase (γGT) elevation (10%) and lymphocytopenia (42%). New grade 3 hyperbilirubinemia occurred in one patient who developed REILD (Fig. 1A). Dynamics in bilirubin, ALP, AST and ALT after radioembolization are depicted in Fig. 1. In the scatter-plot analyses, no correlation was found between toxicities, cumulative PRRT activity and the interval between PRRT and radioembolization.
Radiation-induced gastric ulceration occurred in two patients (5%), both confirmed by endoscopy (one biopsy proven). Radiation pneumonitis occurred in one patient (2%). One patient developed a liver abscess (2%), and one patient developed cholangitis (2%).
Two patients developed REILD as reported by the treating physician; the first patient was previously treated with seven cycles of 177Lu-DOTATATE (55.4 GBq). Whole liver radioembolization in one session with 2.7 GBq was performed 4.6 years after the last cycle of 177Lu-DOTATATE. The patient developed ascites without significant biochemical toxicities and ascites decreased without medical intervention, and thus this was retrospectively classified as grade 2 REILD. Six months after radioembolization, extrahepatic disease progressed and the patient received additional 177Lu-DOTATATE (5.5 GBq), without evidence of REILD.
The second patient was heavily pre-treated and had three cycles of 177Lu-DOTATATE (20.1 GBq). Sequential whole liver radioembolization (right lobe first and left lobe six weeks later) with a cumulative activity of 5.0 GBq (partition model calculation) was performed 3.2 years after the last cycle of 177Lu-DOTATATE. The patient developed abdominal discomfort, ascites, CTCAE grade 3 hyperbilirubinemia and CTCAE grade 2 ALP elevation. Toxicities persisted till the patient died 20 weeks after radioembolization (REILD grade 5).
In retrospect, one other patient developed clinical and biochemical evidence of REILD, but was not reported by the treating physician. The patient had grade 3 REILD, based on grade 2 bilirubin elevation after 4 weeks (at baseline already grade 1) and development of ascites, without evidence of tumour progression. Bilirubin levels returned to grade 1 within 3 months (Fig. 1A) and ascites resolved with additional diuretics (spironolactone and furosemide).
Treatments after both PRRT and Radioembolization
A total of 34/44 patients (77%) received additional treatment after PRRT and radioembolization, apart from the reported additional radioembolization procedures in 10 patients (Table 3). Long-acting SSA therapy was continued in 18/44 patients (41%). In 19/44 patients (43%) additional PRRT treatments were given with 177Lu-DOTATATE with a median of one treatment cycle (range 1–7 cycles) and a median cumulative activity of 9.2 GBq (range 5.5–41.5 GBq). Other treatments were less common and consisted of systemic chemotherapy (27%), surgery (9%) or additional liver-directed therapies (9%; bland-embolization and radiofrequency ablation).
Median OS after radioembolization for the entire population was 3.5 years; range: 51 days (lost to follow-up)–7.6 years [95% CI 1.8–5.1 years]. Median OS for grade 1 NEN was 3.6 years [95% CI 2.7–4.3]. Median OS for grade 2 NEN was 2.8 years [95% CI 0.6–4.6], and for grade 3 NEN was 136 days (range 115–504 days). Patients with an unknown tumour grade had a median OS of 262 days (range 73–644 days).
Kaplan–Meier analyses confirmed intrahepatic tumour load > 75% as a significant negative prognostic factors for OS (p = 0.007; Fig. 2A). Presence of extrahepatic disease resulted in a poorer OS as well; median OS 3.2 years [95% CI 1.1–5.3] versus 6.2 years [95% CI 5.5–7.0] (p = 0.001; Fig. 2B). In the Kaplan–Meier analyses, OS was independent of disease control rate (p = 0.7) or objective response rate (p = 0.7) according to RECIST 1.1.