Caren van Roekel

262 Chapter 10 Theoretically, the combination of systemic treatment and a local therapy may be beneficial. The possible benefit of radioembolization as an addition to systemic therapy in the first line was investigated in the SIRFLOX, FOXFIRE and FOXFIRE- Global studies. Patients with unresectable disease who did not receive prior systemic therapy were randomized to FOLFOX (5-Fluorouracil combined with oxaliplatin) alone or FOLFOX plus radioembolization. In total, 1103 patients were included. Overall progression-free survival (11.0 versus 10.3 months) and overall survival (22.6 versus 23.3 months) were not significantly different between the combination group versus the FOLFOX alone group. There was a statistically significant difference in cumulative incidence of first progression in the liver (22% in the FOLFOX plus radioembolization group versus 39% in the FOLFOX alone group) (35). Based on the results of these studies, treatment with radioembolization in a first-line setting cannot be recommended. However, the results of these trials should be interpreted with caution, as there were flaws in the study design with regard to the dosimetry used and patient selection. The body surface area (BSA) method (see below) was used for activity calculation. This method often leads to under- or overdosing (36). In the FOLFOX study, underdosing was most often the case, since activity was reduced based on tumor involvement and lung shunt fraction (35). Furthermore, a large percentage of included patients had extrahepatic disease at baseline, which is a known dismal prognostic factor, also for treatment with radioembolization (37, 38). Radioembolization in the first-line setting may still be of value, for example in frail, elderly patients. In this patient population, first-line systemic treatment generally consists of capecitabine with bevacizumab. However, the risk of adverse events is higher in elderly patients. In a comparative study on patients treated with capecitabine, the incidence of grade 3 or 4 adverse events was higher in patients ≥80 years compared with the overall population (60% versus 40%) (39). The addition of bevacizumab to capecitabine is associated with a longer progression-free survival (9 months versus 5 months for monotherapy), but also with more side effects, especially hemorrhage (25% versus 7%) and venous thromboembolic events (12% versus 5%), as shown in the AVEX trial in chemotherapy-naïve, elderly patients (40). Radioembolization is as efficient in younger patients as it is in the elderly and the side effects are usually mild (41, 42). Therefore, it would be interesting to study radioembolization as a substitute for systemic treatment in the first line in a select group of patients.