www.thelancet.com/oncology Published online August 3, 2017...

www.thelancet.com/oncology Published online August 3, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30589-2 1
Lancet Oncol 2017
PublishedOnline August 3, 2017

Selective internal radiotherapy in advanced colorectal
cancer: only for right-sided tumours?

Colorectal cancer is a biologically unique tumour entity; in 30–40% of patients, metastases are confined exclusively to the liver, lung, or both, with or without minor additional lymph node involvement. Different from all other tumour types, R0-resection of these lesions is not always followed by systemic relapse in other regions, therefore this local approach is—despite systemic spread of the disease—leads to a potentially
curative resection in up to 61% of patients.1,2 Therefore, locoregional treatment of metastases is of key
importance.
If surgery alone is not appropriate, other locoregional modalities can be given,3 such as hepatic arterial infusion of floxuridine, mitomycin, and oxaliplatin; addition of starch microspheres or application of drug-coated glass beads (eg, irinotecan beads) for prolonged arterial drug exposure; chemoembolisation (transarterial chemo-embolization; TACE); ablation-techniques (eg, radio-frequency, ultrasound, laser-ablation, heat-ablation, or cryoablation, radiosurgery, and brachytherapy [yttrium-90 resin microspheres; selective internal radiotherapy; SIRT]). However, randomised trials testing the individual value of any one treatment are rare; only radiofrequency ablation with or without surgical resection plus chemotherapy has been prospectively proven effective for superior overall survival versus chemotherapy alone (phase 3 CLOCC trial4
).
Beyond this, SIRT also showed clinically relevant efficacy on liver metastases in three small randomised trials in patients refractory to standard systemic chemotherapy; therefore, a broad investigation in first-line therapy was justified. In The Lancet Oncology, Harpreet Wasan and colleagues5report the results of a combined analysis of three trials of first-line FOLFOX (leucovorin, fluorouracil, and oxaliplatin) chemotherapy with or without SIRT. Eligibility criteria used in the three trials were more or less comparable, including patients with unresectable, but limited, liver metastases, with or without lung metastases, and with or without lymph
node metastases.6As expected, the local effect of SIRT is clear, with an improved proportion of patients achieving an overall response and liver-only progression. However, this locoregional effect did not translate into improved overall progression-free survival or overall survival, even in those patients with metastases restricted to the liver (one third of the patients). This result suggests that the biology of the disease is only transiently changed by the locoregional SIRT treatment.
Why does this proven effective locoregional approach not alter the overall course of disease, even in liver-only
disease? Several potential contributing factors that caused imbalance between the groups might have been
involved, including different eligibility criteria in each of the three trials, different oxaliplatin dose between treatment groups (29% less in the FOLFOX plus SIRT group in cycles 1–3 than in the FOLFOX alone group), lower dose of bevacizumab starting 2–3 months later i/n the FOLFOX plus SIRT group, fewer patients who had bevacizumab in the FOLFOX plus SIRT group compared with the FOLFOX alone group (197 [36%] vs 256 [47%]),
less salvage treatment in the FOLFOX plus SIRT group, and heterogeneity of the SIRT dose between patients, centres, and treatment times. However, these factors alone cannot explain the absence of overall benefit from SIRT. More relevant factors might be the fact 47 (8%) of 554 patients randomly assigned to SIRT did not receive SIRT, that 41 (7%) patients only had unilobar application, and 18 (3%) patients crossed over from
FOLFOX alone to FOLFOX plus SIRT. However, even if those patients are eliminated from the analysis, the
overall outcome would not change substantially.
Another relevant factor might be the short overall survival of patients in all three trials, which was shorter
than that of other trials with comparable patient populations but that included treatment with one or
two targeted drugs (bevacizumab and EGFR inhibitors).7In the FOXFIRE trials, EGFR inhibitors were not used and VEGF inhibitors were used in only one third of patients. Additionally, fewer secondary metastases resections were done in the FOXFIRE trials. This difference is mainly due to the enrolment and treatment era of the largest trial included in the analysis, SIRFLOX (2006–13) and also the fact that patients were treated in countries without routine access to the targeted drugs. However, if systemic treatment is weak as in this case, shouldn’t SIRT have a bigger effect on overall survival? This is Colorectal cancer is a biologically unique tumour entity; in 30–40% of patients, metastases are confined exclusively to the liver, lung, or both, with or without minor additional lymph node involvement. Different from all other tumour types, R0-resection of these lesions is not always followed by systemic relapse in other regions, therefore this local approach is—despite systemic spread of the disease—leads to a potentially curative resection in up to 61% of patients.1,2 Therefore, locoregional treatment of metastases is of key importance.If surgery alone is not appropriate, other locoregional modalities can be given,3such as hepatic arterial infusion of floxuridine, mitomycin, and oxaliplatin; addition of starch microspheres or application of drug-coated glass beads (eg, irinotecan beads) for prolonged arterial drug exposure; chemoembolisation (transarterial chemo-embolization; TACE); ablation-techniques (eg, radio-frequency, ultrasound, laser-ablation, heat-ablation, or cryoablation, radiosurgery, and brachytherapy [yttrium-90 resin microspheres; selective internal radiotherapy; SIRT]). However, randomised trials testing the individual value of any one treatment are rare; only radiofrequency ablation with or without surgical resection plus chemotherapy has been prospectively proven effective for superior overall survival versus chemotherapy alone (phase 3 CLOCC trial4 ).Beyond this, SIRT also showed clinically relevant
efficacy on liver metastases in three small randomised trials in patients refractory to standard systemic
chemotherapy; therefore, a broad investigation in first-line therapy was justified.

In The Lancet Oncology, Harpreet Wasan and colleagues5report the results of a combined analysis of three trials of first-line FOLFOX (leucovorin, fluorouracil, and oxaliplatin) chemotherapy with or without SIRT. Eligibility criteria used in the three trials were more or less comparable, including patients with unresectable, but limited, liver metastases, with or without lung metastases, and with or without lymph node metastases.6
As expected, the local effect of SIRT is clear, with an improved proportion of patients achieving an overall response and liver-only progression. However, this locoregional effect did not translate into improved
overall progression-free survival or overall survival, even in those patients with metastases restricted to the liver (one third of the patients). This result suggests that the biology of the disease is only transiently changed by the locoregional SIRT treatment.
Why does this proven effective locoregional approach not alter the overall course of disease, even in liver-only
disease? Several potential contributing factors that caused imbalance between the groups might have been
involved, including different eligibility criteria in each of the three trials, different oxaliplatin dose between
treatment groups (29% less in the FOLFOX plus SIRT group in cycles 1–3 than in the FOLFOX alone group),
lower dose of bevacizumab starting 2–3 months later in the FOLFOX plus SIRT group, fewer patients who had
bevacizumab in the FOLFOX plus SIRT group compared with the FOLFOX alone group (197 [36%] vs 256 [47%]),
less salvage treatment in the FOLFOX plus SIRT group, and heterogeneity of the SIRT dose between patients,
centres, and treatment times. However, these factors alone cannot explain the absence of overall benefit from
SIRT. More relevant factors might be the fact 47 (8%) of 554 patients randomly assigned to SIRT did not
receive SIRT, that 41 (7%) patients only had unilobar application, and 18 (3%) patients crossed over from
FOLFOX alone to FOLFOX plus SIRT. However, even if those patients are eliminated from the analysis, the
overall outcome would not change substantially.
Another relevant factor might be the short overall survival of patients in all three trials, which was shorter
than that of other trials with comparable patient populations but that included treatment with one or two targeted drugs (bevacizumab and EGFR inhibitors).7
In the FOXFIRE trials, EGFR inhibitors were not used and VEGF inhibitors were used in only one third of patients.
Additionally, fewer secondary metastases resections were done in the FOXFIRE trials. This difference is mainly
due to the enrolment and treatment era of the largest trial included in the analysis, SIRFLOX (2006–13) and
also the fact that patients were treated in countries without routine access to the targeted drugs. However,
if systemic treatment is weak as in this case, shouldn’t SIRT have a bigger effect on overall survival? This is obviously not the case, because, beyond the local treatment only, complete metastases resection after
optimal and highly active chemotherapy can improve the long term outcome.4
Furthermore, although the local SIRT approach improved frequency of resection, it only marginally increased the depth of response, the most important prerequisite for complete secondary resection. Therefore, the frequency of secondary resection of liver (and lung) metastases was not sufficiently increased to improve survival.
However, in an important subgroup analysis,8 SIRT was shown to significantly improve overall survival (p=0·007) and progression-free survival (p=0·053) in one third of patients with right-sided primary tumours,
known to be much less sensitive to all types of systemic treatment versus left sided tumours, but had no effect in patients with left-sided primary tumours.SIRT, which is not affected by chemoresistance in the same way,
appears to overcome the intrinsic chemoresistance of liver metastases of right-sided primary tumours. This
is an important message from Wasan and colleagues’ study, the HR for overall survival in patients with
right-sided tumours was 0·67 (0·48–0·92) versus non-significant for left-sided tumours, which could have an
impact on further clinical research, to improve the poor outcome of patients who have right-sided tumours.
Further research into SIRT and also other locoregional approaches, together with optimal systemic chemo-
therapy in this patient group, is now more than justified.
For patients with left-sided primary tumours, SIRT is not an option in first-line treatment. However, the potential indication for salvage treatment with SIRT in non-first-line treatment is not affected by these findings.