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Selective internal radiation therapy for liver metastases from colorectal cancer
Cancer Treatment Reviews 50 (2016) 148–154
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Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
Systematic or Meta-analysis Studies
Selective internal radiation therapy for liver metastases from colorectal cancer Amanda R. Townsend a,⇑, Li Chia Chong b,c, Christos Karapetis d, Timothy J. Price a a
Medical Oncology, The Queen Elizabeth Hospital and University of Adelaide, Woodville, Adelaide, Australia North Adelaide Oncology and Haematology, North Adelaide, Australia c Royal Adelaide Hospital, Adelaide, Australia d Medical Oncology, Flinders Medical Centre and Flinders University, Bedford Park, Adelaide, Australia b
a r t i c l e
i n f o
Article history: Received 18 March 2016 Received in revised form 2 September 2016 Accepted 3 September 2016
Keywords: Yttrium spheres Colorectal cancer Survival Review
a b s t r a c t Liver metastases are often the dominant site of metastatic disease in colorectal cancer. Selective internal radiation therapy (SIRT) involves embolising radiolabeled spheres (SIR-Spheres) into the arterial supply of the liver. This review assesses the effectiveness and toxicity of SIRT in the treatment of metastatic colorectal cancer liver metastasis when given alone or with systemic or regional hepatic artery chemotherapy. We reviewed only randomised controlled trials comparing SIRT and chemotherapy (systemic and/or regional) with chemotherapy alone, or comparing SIRT alone with best supportive care. Only four randomized trials were identified. Due to heterogeneity of the patients and treatments received it was not possible to perform a formal meta-analysis, therefore this is a descriptive analysis only. All studies included patients with either liver only or liver dominant metastatic colorectal cancer. Two trials compared SIRT alone and SIRT with chemotherapy first line. The first with only 21 patients revealed a significant improvement in PFS and median survival with SIRT. The larger second study SIRFLOX of 530 patients comparing SIRT and current standard first line FOLFOX chemotherapy (+/ bevacizumab) with standard FOLFOX +/ bevacizumab alone. There was no improvement in overall PFS with addition of SIRT. In chemotherapy refractory patients SIRT and systemic chemotherapy (fluorouracil) improved progression free survival but not overall survival. A final study (63 patients) compared SIRT and regional chemotherapy (floxuridine) with regional chemotherapy alone in first line showed no significant difference in progression free survival and median survival. There remains a lack of evidence that SIRT improves survival or quality of life in patients with metastatic colorectal cancer. The overall survival results from SIRFLOX combined with FOXFIRE and FOXFIRE Global are awaited. Ó 2016 Elsevier Ltd. All rights reserved.
Introduction Colorectal cancer is the third leading cause of cancer death in the United States and Europe [1,2]. The liver is often the dominant site of metastatic disease and is a significant clinical problem. While resection of liver metastases results in five year survival rates of 30–40% [3] and offers the potential for cure, fewer than 20% of patients with metastatic disease are suitable for resection at diagnosis [4]. Chemotherapy plus or minus biological agents can also result in significant tumour down-staging allowing for subsequent resection of liver metastases. For these patients five year survival of 33% can be achieved. A proportion of patients with initially unresectable liver disease become suitable for resection ⇑ Corresponding author at: The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA, Australia. E-mail address: [email protected] (A.R. Townsend). http://dx.doi.org/10.1016/j.ctrv.2016.09.007 0305-7372/Ó 2016 Elsevier Ltd. All rights reserved.
following systemic chemotherapy (12.5–40%) [5–7]. So although liver resection can achieve long term survival, most patients have extra-hepatic disease or are unresectable due to tumour size and number, location, or inadequate residual liver. For patients with unresectable disease, the 5 year survival remains just over 10% and hence exploration of targeted treatments for liver only or liver dominant disease is potentially important [8]. In an attempt to improve upon the long term outcome for those patients who do not have resectable disease and to achieve better control of liver metastases, multiple loco-regional strategies have been trialed, including radio-frequency ablation, intra-arterial chemotherapy and selective internal radiation therapy (SIRT). Normal liver parenchyma has a poor tolerance to radiation, limiting the ability to use external beam radiotherapy. SIRT involves embolising radiolabeled spheres into the arterial supply of the liver. Tumours within the liver receive their blood supply almost entirely from the hepatic artery whereas the normal liver
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is supplied mainly from the portal vein. Therefore, infusion of radiolabeled microspheres into the arterial system results in delivery of effective doses of radiation to the tumour without causing intolerable toxicity to the normal liver [9,10]. Yttrium-90 is a high energy beta particle emitting radioisotope that can be incorporated into glass or resin microspheres. There is one commercially available product for use in colorectal cancer liver metastases. This is the SIRSphere (SIRTex Medical, Sydney, Australia), which is a resin microsphere with an average diameter of 32 lm ± 10 lm embedded with Yttrium-90. Prior to administration an angiogram is performed to ensure that the arterial anatomy is favourable to proceed. Macroaggregate albumin labelled with Technetium 99 m (99mTc-MAA) is then injected into the hepatic artery to determine the degree of shunting from the liver to the lung or gastrointestinal tract. Arterial shunting of greater than 20% is a contraindication to proceeding because of the risk of radiation pneumonitis and gastric/duodenal ulceration. Other recognised toxicities includes abdominal pain, fever, lethargy, fatigue and a transient rise in liver function tests [10,11]. SIR-Spheres received FDA approval for the treatment of hepatic metastases secondary to colorectal cancer in 2002 following a trial of 74 patients by Gray et al. [12]. Patients with non-resectable liver metastases from colorectal cancer where randomised to hepatic artery chemotherapy with floxuridine with or without the addition of SIRT. This study included patients receiving first line treatment and 10 patients who had received prior palliative chemotherapy. Response rate and time to progression of disease within the liver were significantly improved with the addition of SIRT (response rate 18% vs 44% and PFS 9.7 months vs 15.9 months respectively) but there was no improvement in overall survival. Nonrandomised trials of SIRT have shown significant activity in the treatment of liver metastases from colorectal cancer both in combination with chemotherapy and when given alone, in both first line treatment and in the treatment of chemotherapy refractory disease [13–18]. When the appropriate pre-treatment assessments are performed, SIRT has been shown to have tolerable toxicity. The purpose of this review is to summarise randomised controlled trial evidence for the use of SIRT in the management of advanced colorectal cancer. We previously published a Cochrane review in 2009 [19] and this updated review includes subsequently published studies.
Methods We performed an electronic search of MEDLINE (OVID 1966 to 2016) and EMBASE (from 1980 to 2016) using search strategies in Appendix 1. The proceedings of relevant oncology meetings (ASCO from 1985 until 2015, and ASCO GI from 2004 until 2016) and bibliographies of references and reviews were also searched. Articles published in any language were considered for inclusion. The titles and abstracts of every record retrieved were screened independently by two reviewers (AT,TP). The full text article of all potentially eligible trials were then reviewed. We included all randomised controlled trials that included patients with unresectable liver metastases from colorectal cancer assessing the use of SIRT either alone or in combination with systemic chemotherapy, regional chemotherapy or both. The primary endpoint of interest was progression free survival and secondary endpoints; overall survival, tumour response, toxicity/adverse events, quality of life and rate of hepatic resection. Individual patient data was obtained where possible and hazard ratio determined for time to event data. Analysis was performed in order to analyse patients with and without extra-hepatic metastatic disease separately where possible.
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Results Following the planned search 4 randomised controlled studies were identified. The characteristics of the 4 studies, including primary and secondary endpoints are summarized in Table 1 and results are summarized in Table 2. Two studies compared SIRT and systemic chemotherapy with systemic chemotherapy alone in first line treatment. The first study [20] (van Hazel 2004) compared SIRT and fluorouracil and leucovorin (5FU/LV) with 5FU/LV alone in 21 patients. It showed an improvement in PFS in patients randomized to 5FU/LV and SIRT compared with 5FU/LV alone as first line therapy with a PFS of 11.5 months in the SIRT and chemotherapy group compared with 4.6 months in the chemotherapy alone group (p = 0.004). Survival was also improved (median survival 29.4 months versus 11.8 months, p = 0.008), and response rate increased (73% versus 0). The benefit in PFS persisted in the 15 patients without extra-hepatic metastases (HR 0.23 (CI 0.06– 0.96)). The second study [21] (van Hazel 2016), SIRFLOX, an international, multi-centered, open label RCT compared SIRT and mFOLFOX ± bevacizumab with mFOLFOX and bevacizumab as first line treatment in 530 chemo-naïve mCRC patients with liver metastases plus or minus limited extrahepatic metastasis (fewer than 5 lung nodules of 61 cm diameter or a single nodule of 61.7 cm diameter, and/or lymph node involvement with a single anatomic area of <2 cm diameter). Extrahepatic disease had a predefined limit of 40%. 530 patients were randomized from Oct 2006 to April 2013 to either mFOLFOX ± bevacizumab or mFOLFOX ± bevacizumab + SIRT with a median follow up of 36.1 months. The primary end point was progression free survival at any site as assessed by independent centralized radiology review and secondary end points summarized in Table 1. Patient characteristics were well balanced and median age was 63 years. Extra hepatic metastasis was present in 40% of cases in both arms. Interestingly 90% of patients had synchronous metastases at the time of diagnosis and 45% had their primary tumour in situ. 18 (7%) patients could not have SIRT after randomization and 3 (1%) did not receive any study treatment due to compromised performance status, serious adverse events or disease progression before study treatment. PFS at any site was similar in both arms (median PFS control 10.2 months vs SIRT 10.7 months; HR 0.93; 95% CI; 0.77–1.12, P = 0.43). There was also no difference in overall response rate at any site 68.0% vs 76.4% in control and SIRT arm respectively (P = 0.113). Overall response rate in the liver was improved with the addition of SIRT 68.8% vs 78.7%; P = 0.042 but there was no improvement in liver resection rate after treatment (13.7% vs 14.2%, p = 0.857). Planned subgroup analysis of patients with liver only metastatic disease did not show any improvement in progression free survival (n = 318, HR 0.9 (0.70–1.15)). Overall survival data is expected to be presented in 2017 as a combined analysis with the FOXFIRE and FOXFIRE Global studies to give enough statistical power to detect meaningful impact of SIRT. Beyond first line, a single study randomized 44 patients to SIRT and systemic chemotherapy (fluorouracil) or systemic chemotherapy alone in the treatment of chemotherapy refractory metastatic colorectal cancer (third line treatment) with liver only disease [22] (Hendlisz 2010). The median progression free survival was 4.5 months in the SIRT and chemotherapy group compared with 2.1 months in the chemotherapy alone group (p = 0.03). There was no significant benefit in survival with the addition of SIRT (p = 0.8, median survival chemo + SIRT: 10 months vs. chemo: 7.3 months), however 10 patients in the chemotherapy alone arm subsequently received SIRT monotherapy. The objective response rate was not significantly improved with the addition of SIRT and remained low (chemo + SIRT: 10% vs chemo: 0%, p = 0.22), although one patient in the SIRT arm subsequently underwent surgical resection of metastases.
PFS Response rate Overall survival Toxicity
Time to liver progression Response rate in liver Response rate at any site Liver resection rate Site of first progression
Time to liver progression
PFS at any site
No extrahepatic disease Following failure of 5FU, irinotecan and oxaliplatin (n = 46)
First line (n = 530)
62 vs 62
63 vs 63
Chemo (5FU) + SIRT vs chemo
Chemo (mFOLFOX ± Bevacizumab) + SIRT vs Chemo
Hendlisz 2010
Van Hazel 2016
Extrahepatic disease present in 40% Chemo + SIRT: 108 Chemo: 104
PFS Site of first progression Overall survival Quality of Life Response rate Toxicity Extrahepatic disease disease present in 6 Chemo + SIRT: 2 Chemo: 4 First line (n = 21) 64 vs 65 Chemo (5FU/LV) + SIRT vs chemo alone Van Hazel 2004
Individual patients data available
Primary endpoint OS in original trial design amended to RR and liver PFS due to low recruitment Individual patient data available. 11 patients received prior chemotherapy (6 first line, 5 ‘bridging’) and excluded Overall survival Toxicity Quality of Life Response rate Time to liver progression 59 vs 61 HAC + SIRT vs HAC alone Gray 2001
First line (n = 63) or second line (n = 11)
Extrahepatic disease present in 41 HAC + SIRT: 27 HAC: 14
Comments Secondary endpoints Primary endpoint Extra-hepatic disease Line of therapy Median age Intervention Study
Table 1 Randomised trials.
No individual patients data available 18 of 267 (7%) were not able to receive SIRT and 3 of 267 (1%) did not receive any study treatment as a consequence of compromised performance status, serious AEs or disease progression before study treatment Overall survival and quality of life data not yet published
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No individual patients data available 2 patients in SIRT + 5FU arm ineligible. Results on 44 eligible patients published 10 patients in chemotherapy arm subsequently received SIRT
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The final randomised study [12] (Gray 2001) compared SIRT and regional hepatic artery chemotherapy (floxuridine) with regional chemotherapy alone in a total of 74 patients including 41 patients with extra hepatic disease. 63 of the 74 patients had not received any prior first line therapy. Of the remaining 11 patients 6 had failed prior first line chemotherapy and 5 patients received ‘bridging’ chemotherapy while awaiting entry into the study. As this represented a small, heterogenous group of patients these 11 patients were excluded from the analysis after examining individual data. In the 63 first line therapy patients there was no significant improvement in progression free survival (hepatic or extra-hepatic progression as determined by tumour volume assessment) with the addition of SIRT to regional chemotherapy (p = 0.21, HR 0.72: median PFS chemo + SIRT: 7.3 months vs. chemo: 5.9 months), and no improvement in survival (p = 0.07, HR 0.62: median survival chemo + SIRT: 17.6 months versus chemo: 15.9 months). The objective response rate was 37% with chemotherapy and SIRT compared with 14% for chemotherapy alone (p = 0.051) and one patient in each group underwent resection of liver metastases following study treatment. A total of 22 patients did not have any extra-hepatic disease (8 in the chemotherapy and SIRT group and 14 in the control group). Again, there was no significant benefit in progression free survival or median survival with the addition of SIRT. Toxicity There was increased toxicity with the addition of SIRT to systemic chemotherapy with fluorouracil [20] (Van Hazel 2004) with 13 grade 3 or 4 events in the combination group compared with 5 grade 3 or 4 events in the chemotherapy alone group. In the combination group there was one death due to neutropenic sepsis, one liver abscess, and one patient developed radiation induced cirrhosis. In the SIRFLOX study [21] (Van Hazel 2016), there were also more adverse events P grade 3 in the combination chemotherapy and SIRT arm (85.4% vs 73.3%). The most common toxicities were haematologic (51.2% vs 32.9%); neutropenia (40.7% vs 28.5%), and thrombocytopenia (9.8% vs 2.6%). Fatigue (10.6% vs 4.8%), nausea/ vomiting (8.1% vs 4.1%) and abdominal pain (7.7% vs 2.6%) were also higher in the combination arm. SIRT associated adverse events (gastric/duodenal ulcer, ascites, hepatic failure and radiation hepatitis) were reported in 9 patients (3.7%) and was predominantly medically managed. 5 patients (1.9%) and 9 patients (3.7%) experienced grade 5 adverse events in the chemotherapy and combination chemotherapy and SIRT arm respectively (P = 0.279). Four treatment related grade 5 adverse events were due to chemotherapy, two attributed to SIRT and one was attributed to both chemotherapy and SIRT. In contrast, there was no significant increase in toxicity with the addition of SIRT to systemic chemotherapy in chemotherapy refractory disease [22] (Hendlisz 2010) with only 1 grade 3 event in the combination group and 6 in the chemotherapy alone group, with no grade 4 events reported. However this was a much smaller study. There was also no significant increase in toxicity with the addition of SIRT to regional chemotherapy [12] (Gray 2001) with 23 grade 3 or 4 events reported in both groups, although slightly more patients in the SIRT and regional chemotherapy group experienced grade 1 or 2 nausea or diarrhoea (16 compared with 11 in the regional chemotherapy alone group). Quality of life Two studies assessed quality of life at baseline and then at three monthly intervals [20] (van Hazel 2004) used the 23 point Functional Living Index-Cancer questionnaire (FLIC) and found no
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A.R. Townsend et al. / Cancer Treatment Reviews 50 (2016) 148–154 Table 2 Outcomes of randomized trials. Study
Median progression free survival
Median overall survival
Response rate
Gray 2001
All patients (n = 63) 7.3 vs 5.9 months HR 0.72 (CI 0.43–1.21) No extrahepatic disease (n = 22) 2.7 vs 4.3 months HR 0.72 (CI 0.27–1.90)
All patients (n = 63) 17.6 vs 15.6 months HR 0.62 (CI 0.37–1.05) No extrahepatic disease (n = 22) 14.2 vs 15.6 months HR 0.54 (CI 0.20–1.44)
All patients (n = 63) 37% vs 14% (P = 0.051)
All patients (n = 21) 11.5 vs 4.6 months HR 0.23 (CI 0.08–0.68) No extrahepatic disease (n = 15) 19.1 vs 4.9 months HR 0.23 (CI 0.06–0.96)
All patients (n = 21) 29.4 vs 11.8 months HR 0.22 (CI 0.07–0.74) No extrahepatic disease (n = 15) 31.9 vs 13.8 months HR 0.24 (CI 0.06–0.99)
All patients (n = 21) 73% vs 0% (p = 0.001)
Hendlisz 2010 Chemo + SIRT vs Chemo
No extrahepatic disease (n = 63) 4.5 vs 2.1 months HR 0.51 (CI 0.28–0.94)
No extrahepatic disease (n = 63) 10.0 vs 7.3 months HR 0.92 (CI 0.47–1.78))
No extrahepatic disease (n = 63) 10% vs 0% (p = 0.22)
Van Hazel 2016
All patients (n = 530) 10.7 vs 10.2 months HR 0.93; (CI, 0.77–1.12) No extrahepatic disease (n = 318) HR 0.9 (0.70–1.15)
Data not yet published
All patients (n = 530) 76.4% vs 68.1% (P = 0.113)
HAC + SIRT vs HAC
Van Hazel 2004
Chemo + SIRT vs Chemo
Chemo + SIRT vs Chemo
change from baseline (p = 0.96) but did not report the effect of treatment on quality of life [12] (Gray 2001) used a 13 point linear analogue self assessment scale and reported no decline in quality of life during treatment and no significant difference between the two treatment groups [22] (Hendlisz 2010) did not assess quality of life. SIRFLOX study did not report QOL data as analysis is still ongoing.
Discussion This systematic review on the use of SIRT for the treatment of liver metastases from colorectal cancer shows that there is limited evidence that the addition of SIRT to systemic or regional chemotherapy improves overall progression free survival, and there have been no studies adequately powered to assess overall survival. There are two randomised controlled studies comparing SIRT and systemic chemotherapy with systemic chemotherapy alone as first line therapy. While Van Hazel et al. [20] showed an improvement in progression free survival and overall survival with the addition of SIRT to 5FU/LV it is difficult to make any definite conclusions regarding these results due to the small number of patients. In addition, fluorouracil and leucovorin would no longer be considered the standard treatment for metastatic colorectal cancer. To get further insight into the interaction of SIRT with current doublet chemotherapy (mFOLFOX) ± bevacizumab, the SIRFLOX study was designed. The addition of SIRT to standard first line chemotherapy failed to improve overall PFS. However, the study also included liver only PFS as a secondary endpoint as a novel measure of assessing changes in progression patterns which has been reinforced by recent reviews [23]. There was a 7.9 month improvement in liver PFS (HR 0.69; 95% CI 0.55–0.90; p = 0.002) corresponding to a 31% risk reduction, however this improvement in liver PFS did not result in any improvement in liver resection rate. In a planned subgroup analysis of patients with liver limited disease there was no improvement in overall PFS and an increase in the incidence of progression within the lungs in this group. It is therefore uncertain whether any improvement in liver PFS would impact on overall survival. As the authors noted, this was the first time ‘‘PFS in the liver” has been reported and thus cross trial interpretation is difficult. Understanding the extra-hepatic disease at diagnosis and at progression may however be relevant
No extrahepatic disease (n = 22) 25% vs 14% (p = 0.60)
No extrahepatic disease (n = 15) 78% vs 0% (0.007)
as there is evidence that lung metastases from colorectal cancer behave in a more indolent fashion. Hence liver PFS may be important in this setting where the more aggressive site of metastasis is controlled, and the more indolent and potentially lower volume disease progresses with less impact on survival [24]. This is hypothetical however although it is the premise behind increasing rates of liver surgery in the setting of coexistent low volume lung metastasis [25]. Furthermore this hypothesis was used by the authors of the Phase II randomised CLOCC study to explain the OS gain with radiofrequency ablation combined with chemotherapy. The authors suggested the reduced rate of liver metastasis as first site of recurrence (45% vs 76%, p = 0.0001) as a factor in the improved OS. Importantly overall PFS was also improved by the addition of RFA, which differs to the results of SIRFLOX, and thus direct comparison is difficult [26]. Ultimately the ongoing randomized studies using oxaliplatin based chemotherapy in combination with SIRT (FOXFIRE and FOXFIRE Global) will provide important additional information in this setting [27] and will then trigger a planned combined OS analysis in 2017. Global recruitment was completed in January 2015 and we are awaiting results in the first half of 2017 (www.SIRTEX.com). Moreover, subgroup analysis will also provide insight into the benefit of SIRT for poor prognostic groups like RAS/ RAF mutant patients. This analysis is awaited. There is only one randomised controlled study comparing SIRT and systemic chemotherapy with systemic chemotherapy alone in the treatment of chemotherapy refractory disease [22] (Hendlisz 2010). In this study, progression free survival was doubled (median 2.1 vs 4.5 months) but there was no statistically significant benefit on overall survival (median 7.3 vs 10.0 months). While this is a small single study these survival figures are similar to that seen in a prospective uncontrolled phase II study of SIRT in chemotherapy refractory disease in which median PFS was 3.7 months and median overall survival 12.6 months [17] and in a prospective matched pair analysis in which median PFS was 5.5 months (vs 2.1 months) and median overall survival 8.3 months [28]. Hendlisz 2010 [22] did not show a survival benefit for the addition of SIRT but this may be due to the small numbers in this study and a lack of power to detect a significant difference. This study included patients who were resistant or intolerant to standard chemotherapy (5FU, oxaliplatin and irinotecan) but unfortunately did not collect data on whether patients were truly refractory or how many lines of therapy they had received. While 12 patients
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in this study had previously received an EGFR inhibitor and a further 8 subsequently received an EGFR inhibitor, KRAS testing was not routine and EGFR antagonists were not readily available at the time of the study. Future studies assessing the benefit of SIRT in patients who are refractory to all standard therapy, including biological agents such as bevacizumab and EGFR inhibitors, will become increasingly difficult due to slow recruitment and ongoing development of new agents in the refractory setting such as regorafenib and TAS-102 [28,29]. There is only one randomised controlled study comparing SIRT and regional chemotherapy with regional chemotherapy alone [12] (Gray 2001). The published data reports an improvement in time to progressive disease in the liver with the addition of SIRT (15.9 months vs. 9.7 months, p = 0.001). However, this study did not show any significant improvement in systemic progression or overall survival with the addition of SIRT as first line therapy (median progression free survival 7.3 months vs 5.9 months, p = 0.21). In this review, we separately analysed the outcomes of those patients without extra-hepatic disease (n = 41). There was no statistically significant difference between those receiving SIRT and regional chemotherapy compared with those receiving regional chemotherapy alone however no conclusions can be drawn from this small group. Response rate is an important clinical endpoint in patients with liver metastases, particularly for the small subgroup of patients who may become suitable for liver resection if downstaging can be achieved. The overall response rate with the addition of SIRT to mFOLFOX ± bevacizumab was not significantly different to mFOLFOX ± bevacizumab alone (76.4% vs 68.1%; P = 0.113). In the liver only subset, the overall response rate was significantly improved with the addition of SIRT (78.7% vs 68.8%; P = .042). However, despite the improvement in overall response rate in the liver, the resection rate did not differ with or without SIRT. 36 patients (13.7%) underwent liver resection in the chemotherapy arm compared with 38 patients (14.2%) in the SIRT arm (P = .857). Two studies [20,22] (van Hazel 2004, Hendlisz 2010) combining SIRT with fluoropyrimidine-based chemotherapy also showed improved response rate from 0% to 9.5% in the chemotherapy refractory setting and 0% to 73% in the first line setting but this did not translate into an improvement in overall survival or liver resection rates in either study. It is unclear why the improvement in response rate in the liver has not translated into improved resection rate, whether this reflects reluctance of surgeons to perform hepatic surgery following SIRT, disease distribution or progression of extrahepatic disease. In the palliative treatment of metastatic cancer, toxicity and the impact on quality of life are important endpoints. The addition of SIRT to systemic chemotherapy did result in increased toxicity in the two first line studies [20,21] (Van Hazel 2004, 2016) with higher rates of haematologic toxicities and SIRT related toxicities such as nausea, vomiting, abdominal pain, radiation hepatitis and hepatic failure. The relative high rate of Pgrade 3 adverse events (85.4%) in SIRFLOX study did not result in an improvement in overall PFS. There is a lack of long term follow up of toxicities in this study as the patients were monitored until death or a maximum of 5 years only. There is potential for late radiation effects associated with SIRT such as liver fibrosis [30] and its impact on survival is uncertain. The incidence of delayed toxicity rate was reported in only two phase II studies and three observational studies and ranges from 4 to 10% [17,18,30–32]. Most common delayed toxicities were gastrointestinal ulceration and liver dysfunction. Gastrointestinal ulceration occurs more commonly than liver dysfunction at a rate of 3–4% of grade 1 or 2 toxicities [17]. Liver dysfunction were mainly secondary to grade 3 or 4 radiation induced biliary strictures [18]. However, delayed toxicity rates were only reported in a small number of studies and interpreting whether
grade 3 or 4 liver dysfunction was treatment or disease related is difficult. Quality of life data was only available for two studies [20,12] (Van Hazel 2004, Gray 2001). While SIRT did not appear to adversely affect quality of life in either study, both of these studies assessed quality of life at 3 monthly intervals and are therefore unlikely to have captured the early, likely negative, impact of SIRT on quality of life which needs to be considered when determining its benefit as a palliative treatment. Assessing quality of life immediately following SIRT administration and at one month in future studies may provide more useful data. QOL data for the larger SIRFLOX study has not yet been presented and unfortunately, no quality of life data was collected in the study of chemotherapy refractory disease [22] (Hendlisz 2010) where this is a particularly important endpoint. One prospective phase II study in this setting collected quality of life data [17] and did not show any adverse effect of SIRT on quality of life at 6 weeks. However, only 14 of the 50 patients enrolled in this study completed the questionnaires so these results may be biased. There are a number of other liver directed therapies available for liver dominant metastatic colorectal cancer including radiofrequency ablation (RFA), transarterial chemoembolization (TACE) and stereotactic body radiation therapy (SBRT). The evidence for other liver directed therapies is based predominantly on phase II studies and small randomised trials. The phase II CLOCC study assessed the benefit of RFA. 119 patients were randomised to receive systemic chemotherapy (FOLFOX (±bevacizumab)) in combination with RFA or chemotherapy alone (Ruers et al., 2012) and showed an improvement in PFS rate at 3 years (27.6% vs 10.6%, P = 0.025) [33]. Although this study has demonstrated a survival advantage with the addition of RFA to systemic therapy in the updated results (median survival 45.6 months vs 40.5 months, HR 0.58, 95% CI: 0.38–0.88, P = 0.01) whether RFA alone accounted for the entirety of the observed benefits seen is unclear as patients in the RFA group more often underwent additional resection of selected liver lesions and had better prognostic characteristics compared to the patients in the control group. The final full updated publication is awaited. TACE involves hepatic artery catheterization to cause vessel occlusion with locally delivered chemotherapy. A recent prospective study randomised 74 patients with colorectal metastases who failed oxaliplatin to drug eluting beads loaded with irinotecan (DEBIRI) versus FOLFIRI. The DEBIRI group had significantly improved median survival of 22 months compared to 15 months for the FOLFIRI group (p = 0.031). Toxicities of DEBIRI includes abdominal pain, fever, nausea and liver dysfunction [34]. Stereotactic body radiation therapy (SBRT) allows delivery of highly focused radiation with extreme precision. The local control rates in the liver at 1 and 2 years for SBRT are 67–100% and 55–92%. Overall there is a lack of large randomized studies assessing the benefit of liver directed therapy and to our knowledge, no trials directly comparing different liver directed strategies. Most of the liver directed therapies require specific medical and surgical oncology expertise and should be recommended only in institutions with extensive experience with the procedure. More widespread use of these techniques has been limited by lack of robust data and the need for a high level of expertise in the individual procedures. The combined analysis of the SIRFLOX and FOXFIRE trials will be the largest randomized study of liver directed therapies and we await the final overall survival analysis with interest.
Conclusions There remains a lack of evidence that SIRT improves survival or quality of life in patients with metastatic colorectal cancer,
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whether given alone, or with systemic or regional chemotherapy in first line therapy. The overall survival analysis of the three current first line studies planned for 2017 will hopefully give clinicians guidance as to the role of SIRT in chemo-naive patients. SIRT should therefore continue to be offered to patients within clinical trials in this setting. Results in the chemotherapy pre-treated group are suggestive of a benefit in progression free survival but there is no proven benefit on overall survival. There remains a need to explore the benefit in those truly resistant to chemotherapy and biological agents with a focus on quality of life in this group. Declarations of interest Professor Timothy Price is a member of Advisory Board for Roche, AMGEN, Bayer and Merck. Dr. Christos Karapetis is a member of Advisory Board for Roche, AMGEN and Merck. Dr. Amanda Townsend has received research funding from AMGEN. Acknowledgements Professor Adrian Esterman, Foundation Chair of Biostatistics, University of South Australia, for providing statistical analysis. Michael Tapner, Clinical Research Officer, SIRTEX Technology Pty Ltd, for providing individual patient data from Gray 2001 and Van Hazel 2004. Dr Dainik Patel, The Queen Elizabeth Hospital. Appendix 1 The search strategy given below was used to search MEDLINE (OVID) to February 2016. 1. exp Colorectal Neoplasms/ 2. ((colorect* or colon* or rect* or anal* or anus* or intestin* or bowel*) adj3 (carcinom* or neoplas* or adenocarcinom* or cancer* or tumour* or tumour* or sarcom* or adenom*)).mp. 3. #1 or #2 4. exp Liver Neoplasms/ 5. ((liver or hepatic$ or hepato$) adj3 (carcinom* or neoplas* or cancer* or tumour* or tumour* or metastas$)).mp. 6. #4 or #5 7. Yttrium Radioisotopes/ 8. Microspheres/ 9. (selective internal radi$ or SIRT or radioemboli$ or radioemboli$ or SIR-sphere$ or therasphere$ or ((yttrium$ or $yttrium or 90y$ or radiolabel$) adj5 microsphere$)).mp. 10. (intra-arterial or transarterial or arterial infusion or arterial therap$ or chemoemboli$ or (regional adj3 chemotherap $)).mp. 11. #7 or #8 or #9 or #10 12. #3 and #6 and #11 13. randomized controlled trial.pt. 14. controlled clinical trial.pt. 15. randomized.ab. 16. placebo.ab. 17. clinical trial.sh. 18. randomly.ab. 19. trial.ti. 20. #13 or #14 or #15 or #16 or #17 or #18 or #19 21. humans.sh. 22. #20 and #21 23. #12 and #22
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The following search strategy was used to search EMBASE (OVID) to February 2016. 1. exp colorectal tumour/ 2. ((colorect* or colon* or rect* or anal* or anus* or intestin* or bowel*) adj3 (carcinom* or neoplas* or adenocarcinom* or cancer* or tumour* or tumour* or sarcom* or adenom*)).mp. 3. #1 or #2 4. exp liver tumour/ 5. exp liver metastasis/ 6. ((liver or hepatic$ or hepato$) adj3 (carcinom* or neoplas* or cancer* or tumour* or tumour* or metastas$)).mp. 7. #4 or #5 or #6 8. exp yttrium/ 9. exp microsphere/ 10. (selective internal radi$ or SIRT or radioemboli$ or radioemboli$ or SIR-sphere$ or therasphere$ or ((yttrium$ or $yttrium or 90y$ or radiolabel$) adj5 microsphere$)).mp. 11. (intra-arterial or transarterial or arterial infusion or arterial therap$ or chemoemboli$ or (regional adj3 chemotherap $)).mp. 12. #8 or #9 or #10 or #11 13. #3 and #7 and #12 14. randomized controlled trial/ 15. randomization/ 16. controlled study/ 17. multicenter study/ 18. phase 3 clinical trial/ 19. phase 4 clinical trial/ 20. double blind procedure/ 21. single blind procedure/ 22. ((singl* or doubl* or trebl* or tripl*) adj (blind* or mask*)).ti, ab. 23. (random* or cross* over* or factorial* or placebo* or volunteer*).ti,ab. 24. #19 or #16 or #20 or #22 or #15 or #21 or #17 or #14 or #23 or #18 25. ‘‘human*”.ti,ab. 26. (animal* or nonhuman*).ti,ab. 27. #26 and #25 28. #26 not #27 29. #24 not #28 30. #13 and #29
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Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
Systematic or Meta-analysis Studies
Selective internal radiation therapy for liver metastases from colorectal cancer Amanda R. Townsend a,⇑, Li Chia Chong b,c, Christos Karapetis d, Timothy J. Price a a
Medical Oncology, The Queen Elizabeth Hospital and University of Adelaide, Woodville, Adelaide, Australia North Adelaide Oncology and Haematology, North Adelaide, Australia c Royal Adelaide Hospital, Adelaide, Australia d Medical Oncology, Flinders Medical Centre and Flinders University, Bedford Park, Adelaide, Australia b
a r t i c l e
i n f o
Article history: Received 18 March 2016 Received in revised form 2 September 2016 Accepted 3 September 2016
Keywords: Yttrium spheres Colorectal cancer Survival Review
a b s t r a c t Liver metastases are often the dominant site of metastatic disease in colorectal cancer. Selective internal radiation therapy (SIRT) involves embolising radiolabeled spheres (SIR-Spheres) into the arterial supply of the liver. This review assesses the effectiveness and toxicity of SIRT in the treatment of metastatic colorectal cancer liver metastasis when given alone or with systemic or regional hepatic artery chemotherapy. We reviewed only randomised controlled trials comparing SIRT and chemotherapy (systemic and/or regional) with chemotherapy alone, or comparing SIRT alone with best supportive care. Only four randomized trials were identified. Due to heterogeneity of the patients and treatments received it was not possible to perform a formal meta-analysis, therefore this is a descriptive analysis only. All studies included patients with either liver only or liver dominant metastatic colorectal cancer. Two trials compared SIRT alone and SIRT with chemotherapy first line. The first with only 21 patients revealed a significant improvement in PFS and median survival with SIRT. The larger second study SIRFLOX of 530 patients comparing SIRT and current standard first line FOLFOX chemotherapy (+/ bevacizumab) with standard FOLFOX +/ bevacizumab alone. There was no improvement in overall PFS with addition of SIRT. In chemotherapy refractory patients SIRT and systemic chemotherapy (fluorouracil) improved progression free survival but not overall survival. A final study (63 patients) compared SIRT and regional chemotherapy (floxuridine) with regional chemotherapy alone in first line showed no significant difference in progression free survival and median survival. There remains a lack of evidence that SIRT improves survival or quality of life in patients with metastatic colorectal cancer. The overall survival results from SIRFLOX combined with FOXFIRE and FOXFIRE Global are awaited. Ó 2016 Elsevier Ltd. All rights reserved.
Introduction Colorectal cancer is the third leading cause of cancer death in the United States and Europe [1,2]. The liver is often the dominant site of metastatic disease and is a significant clinical problem. While resection of liver metastases results in five year survival rates of 30–40% [3] and offers the potential for cure, fewer than 20% of patients with metastatic disease are suitable for resection at diagnosis [4]. Chemotherapy plus or minus biological agents can also result in significant tumour down-staging allowing for subsequent resection of liver metastases. For these patients five year survival of 33% can be achieved. A proportion of patients with initially unresectable liver disease become suitable for resection ⇑ Corresponding author at: The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA, Australia. E-mail address: [email protected] (A.R. Townsend). http://dx.doi.org/10.1016/j.ctrv.2016.09.007 0305-7372/Ó 2016 Elsevier Ltd. All rights reserved.
following systemic chemotherapy (12.5–40%) [5–7]. So although liver resection can achieve long term survival, most patients have extra-hepatic disease or are unresectable due to tumour size and number, location, or inadequate residual liver. For patients with unresectable disease, the 5 year survival remains just over 10% and hence exploration of targeted treatments for liver only or liver dominant disease is potentially important [8]. In an attempt to improve upon the long term outcome for those patients who do not have resectable disease and to achieve better control of liver metastases, multiple loco-regional strategies have been trialed, including radio-frequency ablation, intra-arterial chemotherapy and selective internal radiation therapy (SIRT). Normal liver parenchyma has a poor tolerance to radiation, limiting the ability to use external beam radiotherapy. SIRT involves embolising radiolabeled spheres into the arterial supply of the liver. Tumours within the liver receive their blood supply almost entirely from the hepatic artery whereas the normal liver
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is supplied mainly from the portal vein. Therefore, infusion of radiolabeled microspheres into the arterial system results in delivery of effective doses of radiation to the tumour without causing intolerable toxicity to the normal liver [9,10]. Yttrium-90 is a high energy beta particle emitting radioisotope that can be incorporated into glass or resin microspheres. There is one commercially available product for use in colorectal cancer liver metastases. This is the SIRSphere (SIRTex Medical, Sydney, Australia), which is a resin microsphere with an average diameter of 32 lm ± 10 lm embedded with Yttrium-90. Prior to administration an angiogram is performed to ensure that the arterial anatomy is favourable to proceed. Macroaggregate albumin labelled with Technetium 99 m (99mTc-MAA) is then injected into the hepatic artery to determine the degree of shunting from the liver to the lung or gastrointestinal tract. Arterial shunting of greater than 20% is a contraindication to proceeding because of the risk of radiation pneumonitis and gastric/duodenal ulceration. Other recognised toxicities includes abdominal pain, fever, lethargy, fatigue and a transient rise in liver function tests [10,11]. SIR-Spheres received FDA approval for the treatment of hepatic metastases secondary to colorectal cancer in 2002 following a trial of 74 patients by Gray et al. [12]. Patients with non-resectable liver metastases from colorectal cancer where randomised to hepatic artery chemotherapy with floxuridine with or without the addition of SIRT. This study included patients receiving first line treatment and 10 patients who had received prior palliative chemotherapy. Response rate and time to progression of disease within the liver were significantly improved with the addition of SIRT (response rate 18% vs 44% and PFS 9.7 months vs 15.9 months respectively) but there was no improvement in overall survival. Nonrandomised trials of SIRT have shown significant activity in the treatment of liver metastases from colorectal cancer both in combination with chemotherapy and when given alone, in both first line treatment and in the treatment of chemotherapy refractory disease [13–18]. When the appropriate pre-treatment assessments are performed, SIRT has been shown to have tolerable toxicity. The purpose of this review is to summarise randomised controlled trial evidence for the use of SIRT in the management of advanced colorectal cancer. We previously published a Cochrane review in 2009 [19] and this updated review includes subsequently published studies.
Methods We performed an electronic search of MEDLINE (OVID 1966 to 2016) and EMBASE (from 1980 to 2016) using search strategies in Appendix 1. The proceedings of relevant oncology meetings (ASCO from 1985 until 2015, and ASCO GI from 2004 until 2016) and bibliographies of references and reviews were also searched. Articles published in any language were considered for inclusion. The titles and abstracts of every record retrieved were screened independently by two reviewers (AT,TP). The full text article of all potentially eligible trials were then reviewed. We included all randomised controlled trials that included patients with unresectable liver metastases from colorectal cancer assessing the use of SIRT either alone or in combination with systemic chemotherapy, regional chemotherapy or both. The primary endpoint of interest was progression free survival and secondary endpoints; overall survival, tumour response, toxicity/adverse events, quality of life and rate of hepatic resection. Individual patient data was obtained where possible and hazard ratio determined for time to event data. Analysis was performed in order to analyse patients with and without extra-hepatic metastatic disease separately where possible.
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Results Following the planned search 4 randomised controlled studies were identified. The characteristics of the 4 studies, including primary and secondary endpoints are summarized in Table 1 and results are summarized in Table 2. Two studies compared SIRT and systemic chemotherapy with systemic chemotherapy alone in first line treatment. The first study [20] (van Hazel 2004) compared SIRT and fluorouracil and leucovorin (5FU/LV) with 5FU/LV alone in 21 patients. It showed an improvement in PFS in patients randomized to 5FU/LV and SIRT compared with 5FU/LV alone as first line therapy with a PFS of 11.5 months in the SIRT and chemotherapy group compared with 4.6 months in the chemotherapy alone group (p = 0.004). Survival was also improved (median survival 29.4 months versus 11.8 months, p = 0.008), and response rate increased (73% versus 0). The benefit in PFS persisted in the 15 patients without extra-hepatic metastases (HR 0.23 (CI 0.06– 0.96)). The second study [21] (van Hazel 2016), SIRFLOX, an international, multi-centered, open label RCT compared SIRT and mFOLFOX ± bevacizumab with mFOLFOX and bevacizumab as first line treatment in 530 chemo-naïve mCRC patients with liver metastases plus or minus limited extrahepatic metastasis (fewer than 5 lung nodules of 61 cm diameter or a single nodule of 61.7 cm diameter, and/or lymph node involvement with a single anatomic area of <2 cm diameter). Extrahepatic disease had a predefined limit of 40%. 530 patients were randomized from Oct 2006 to April 2013 to either mFOLFOX ± bevacizumab or mFOLFOX ± bevacizumab + SIRT with a median follow up of 36.1 months. The primary end point was progression free survival at any site as assessed by independent centralized radiology review and secondary end points summarized in Table 1. Patient characteristics were well balanced and median age was 63 years. Extra hepatic metastasis was present in 40% of cases in both arms. Interestingly 90% of patients had synchronous metastases at the time of diagnosis and 45% had their primary tumour in situ. 18 (7%) patients could not have SIRT after randomization and 3 (1%) did not receive any study treatment due to compromised performance status, serious adverse events or disease progression before study treatment. PFS at any site was similar in both arms (median PFS control 10.2 months vs SIRT 10.7 months; HR 0.93; 95% CI; 0.77–1.12, P = 0.43). There was also no difference in overall response rate at any site 68.0% vs 76.4% in control and SIRT arm respectively (P = 0.113). Overall response rate in the liver was improved with the addition of SIRT 68.8% vs 78.7%; P = 0.042 but there was no improvement in liver resection rate after treatment (13.7% vs 14.2%, p = 0.857). Planned subgroup analysis of patients with liver only metastatic disease did not show any improvement in progression free survival (n = 318, HR 0.9 (0.70–1.15)). Overall survival data is expected to be presented in 2017 as a combined analysis with the FOXFIRE and FOXFIRE Global studies to give enough statistical power to detect meaningful impact of SIRT. Beyond first line, a single study randomized 44 patients to SIRT and systemic chemotherapy (fluorouracil) or systemic chemotherapy alone in the treatment of chemotherapy refractory metastatic colorectal cancer (third line treatment) with liver only disease [22] (Hendlisz 2010). The median progression free survival was 4.5 months in the SIRT and chemotherapy group compared with 2.1 months in the chemotherapy alone group (p = 0.03). There was no significant benefit in survival with the addition of SIRT (p = 0.8, median survival chemo + SIRT: 10 months vs. chemo: 7.3 months), however 10 patients in the chemotherapy alone arm subsequently received SIRT monotherapy. The objective response rate was not significantly improved with the addition of SIRT and remained low (chemo + SIRT: 10% vs chemo: 0%, p = 0.22), although one patient in the SIRT arm subsequently underwent surgical resection of metastases.
PFS Response rate Overall survival Toxicity
Time to liver progression Response rate in liver Response rate at any site Liver resection rate Site of first progression
Time to liver progression
PFS at any site
No extrahepatic disease Following failure of 5FU, irinotecan and oxaliplatin (n = 46)
First line (n = 530)
62 vs 62
63 vs 63
Chemo (5FU) + SIRT vs chemo
Chemo (mFOLFOX ± Bevacizumab) + SIRT vs Chemo
Hendlisz 2010
Van Hazel 2016
Extrahepatic disease present in 40% Chemo + SIRT: 108 Chemo: 104
PFS Site of first progression Overall survival Quality of Life Response rate Toxicity Extrahepatic disease disease present in 6 Chemo + SIRT: 2 Chemo: 4 First line (n = 21) 64 vs 65 Chemo (5FU/LV) + SIRT vs chemo alone Van Hazel 2004
Individual patients data available
Primary endpoint OS in original trial design amended to RR and liver PFS due to low recruitment Individual patient data available. 11 patients received prior chemotherapy (6 first line, 5 ‘bridging’) and excluded Overall survival Toxicity Quality of Life Response rate Time to liver progression 59 vs 61 HAC + SIRT vs HAC alone Gray 2001
First line (n = 63) or second line (n = 11)
Extrahepatic disease present in 41 HAC + SIRT: 27 HAC: 14
Comments Secondary endpoints Primary endpoint Extra-hepatic disease Line of therapy Median age Intervention Study
Table 1 Randomised trials.
No individual patients data available 18 of 267 (7%) were not able to receive SIRT and 3 of 267 (1%) did not receive any study treatment as a consequence of compromised performance status, serious AEs or disease progression before study treatment Overall survival and quality of life data not yet published
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No individual patients data available 2 patients in SIRT + 5FU arm ineligible. Results on 44 eligible patients published 10 patients in chemotherapy arm subsequently received SIRT
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The final randomised study [12] (Gray 2001) compared SIRT and regional hepatic artery chemotherapy (floxuridine) with regional chemotherapy alone in a total of 74 patients including 41 patients with extra hepatic disease. 63 of the 74 patients had not received any prior first line therapy. Of the remaining 11 patients 6 had failed prior first line chemotherapy and 5 patients received ‘bridging’ chemotherapy while awaiting entry into the study. As this represented a small, heterogenous group of patients these 11 patients were excluded from the analysis after examining individual data. In the 63 first line therapy patients there was no significant improvement in progression free survival (hepatic or extra-hepatic progression as determined by tumour volume assessment) with the addition of SIRT to regional chemotherapy (p = 0.21, HR 0.72: median PFS chemo + SIRT: 7.3 months vs. chemo: 5.9 months), and no improvement in survival (p = 0.07, HR 0.62: median survival chemo + SIRT: 17.6 months versus chemo: 15.9 months). The objective response rate was 37% with chemotherapy and SIRT compared with 14% for chemotherapy alone (p = 0.051) and one patient in each group underwent resection of liver metastases following study treatment. A total of 22 patients did not have any extra-hepatic disease (8 in the chemotherapy and SIRT group and 14 in the control group). Again, there was no significant benefit in progression free survival or median survival with the addition of SIRT. Toxicity There was increased toxicity with the addition of SIRT to systemic chemotherapy with fluorouracil [20] (Van Hazel 2004) with 13 grade 3 or 4 events in the combination group compared with 5 grade 3 or 4 events in the chemotherapy alone group. In the combination group there was one death due to neutropenic sepsis, one liver abscess, and one patient developed radiation induced cirrhosis. In the SIRFLOX study [21] (Van Hazel 2016), there were also more adverse events P grade 3 in the combination chemotherapy and SIRT arm (85.4% vs 73.3%). The most common toxicities were haematologic (51.2% vs 32.9%); neutropenia (40.7% vs 28.5%), and thrombocytopenia (9.8% vs 2.6%). Fatigue (10.6% vs 4.8%), nausea/ vomiting (8.1% vs 4.1%) and abdominal pain (7.7% vs 2.6%) were also higher in the combination arm. SIRT associated adverse events (gastric/duodenal ulcer, ascites, hepatic failure and radiation hepatitis) were reported in 9 patients (3.7%) and was predominantly medically managed. 5 patients (1.9%) and 9 patients (3.7%) experienced grade 5 adverse events in the chemotherapy and combination chemotherapy and SIRT arm respectively (P = 0.279). Four treatment related grade 5 adverse events were due to chemotherapy, two attributed to SIRT and one was attributed to both chemotherapy and SIRT. In contrast, there was no significant increase in toxicity with the addition of SIRT to systemic chemotherapy in chemotherapy refractory disease [22] (Hendlisz 2010) with only 1 grade 3 event in the combination group and 6 in the chemotherapy alone group, with no grade 4 events reported. However this was a much smaller study. There was also no significant increase in toxicity with the addition of SIRT to regional chemotherapy [12] (Gray 2001) with 23 grade 3 or 4 events reported in both groups, although slightly more patients in the SIRT and regional chemotherapy group experienced grade 1 or 2 nausea or diarrhoea (16 compared with 11 in the regional chemotherapy alone group). Quality of life Two studies assessed quality of life at baseline and then at three monthly intervals [20] (van Hazel 2004) used the 23 point Functional Living Index-Cancer questionnaire (FLIC) and found no
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A.R. Townsend et al. / Cancer Treatment Reviews 50 (2016) 148–154 Table 2 Outcomes of randomized trials. Study
Median progression free survival
Median overall survival
Response rate
Gray 2001
All patients (n = 63) 7.3 vs 5.9 months HR 0.72 (CI 0.43–1.21) No extrahepatic disease (n = 22) 2.7 vs 4.3 months HR 0.72 (CI 0.27–1.90)
All patients (n = 63) 17.6 vs 15.6 months HR 0.62 (CI 0.37–1.05) No extrahepatic disease (n = 22) 14.2 vs 15.6 months HR 0.54 (CI 0.20–1.44)
All patients (n = 63) 37% vs 14% (P = 0.051)
All patients (n = 21) 11.5 vs 4.6 months HR 0.23 (CI 0.08–0.68) No extrahepatic disease (n = 15) 19.1 vs 4.9 months HR 0.23 (CI 0.06–0.96)
All patients (n = 21) 29.4 vs 11.8 months HR 0.22 (CI 0.07–0.74) No extrahepatic disease (n = 15) 31.9 vs 13.8 months HR 0.24 (CI 0.06–0.99)
All patients (n = 21) 73% vs 0% (p = 0.001)
Hendlisz 2010 Chemo + SIRT vs Chemo
No extrahepatic disease (n = 63) 4.5 vs 2.1 months HR 0.51 (CI 0.28–0.94)
No extrahepatic disease (n = 63) 10.0 vs 7.3 months HR 0.92 (CI 0.47–1.78))
No extrahepatic disease (n = 63) 10% vs 0% (p = 0.22)
Van Hazel 2016
All patients (n = 530) 10.7 vs 10.2 months HR 0.93; (CI, 0.77–1.12) No extrahepatic disease (n = 318) HR 0.9 (0.70–1.15)
Data not yet published
All patients (n = 530) 76.4% vs 68.1% (P = 0.113)
HAC + SIRT vs HAC
Van Hazel 2004
Chemo + SIRT vs Chemo
Chemo + SIRT vs Chemo
change from baseline (p = 0.96) but did not report the effect of treatment on quality of life [12] (Gray 2001) used a 13 point linear analogue self assessment scale and reported no decline in quality of life during treatment and no significant difference between the two treatment groups [22] (Hendlisz 2010) did not assess quality of life. SIRFLOX study did not report QOL data as analysis is still ongoing.
Discussion This systematic review on the use of SIRT for the treatment of liver metastases from colorectal cancer shows that there is limited evidence that the addition of SIRT to systemic or regional chemotherapy improves overall progression free survival, and there have been no studies adequately powered to assess overall survival. There are two randomised controlled studies comparing SIRT and systemic chemotherapy with systemic chemotherapy alone as first line therapy. While Van Hazel et al. [20] showed an improvement in progression free survival and overall survival with the addition of SIRT to 5FU/LV it is difficult to make any definite conclusions regarding these results due to the small number of patients. In addition, fluorouracil and leucovorin would no longer be considered the standard treatment for metastatic colorectal cancer. To get further insight into the interaction of SIRT with current doublet chemotherapy (mFOLFOX) ± bevacizumab, the SIRFLOX study was designed. The addition of SIRT to standard first line chemotherapy failed to improve overall PFS. However, the study also included liver only PFS as a secondary endpoint as a novel measure of assessing changes in progression patterns which has been reinforced by recent reviews [23]. There was a 7.9 month improvement in liver PFS (HR 0.69; 95% CI 0.55–0.90; p = 0.002) corresponding to a 31% risk reduction, however this improvement in liver PFS did not result in any improvement in liver resection rate. In a planned subgroup analysis of patients with liver limited disease there was no improvement in overall PFS and an increase in the incidence of progression within the lungs in this group. It is therefore uncertain whether any improvement in liver PFS would impact on overall survival. As the authors noted, this was the first time ‘‘PFS in the liver” has been reported and thus cross trial interpretation is difficult. Understanding the extra-hepatic disease at diagnosis and at progression may however be relevant
No extrahepatic disease (n = 22) 25% vs 14% (p = 0.60)
No extrahepatic disease (n = 15) 78% vs 0% (0.007)
as there is evidence that lung metastases from colorectal cancer behave in a more indolent fashion. Hence liver PFS may be important in this setting where the more aggressive site of metastasis is controlled, and the more indolent and potentially lower volume disease progresses with less impact on survival [24]. This is hypothetical however although it is the premise behind increasing rates of liver surgery in the setting of coexistent low volume lung metastasis [25]. Furthermore this hypothesis was used by the authors of the Phase II randomised CLOCC study to explain the OS gain with radiofrequency ablation combined with chemotherapy. The authors suggested the reduced rate of liver metastasis as first site of recurrence (45% vs 76%, p = 0.0001) as a factor in the improved OS. Importantly overall PFS was also improved by the addition of RFA, which differs to the results of SIRFLOX, and thus direct comparison is difficult [26]. Ultimately the ongoing randomized studies using oxaliplatin based chemotherapy in combination with SIRT (FOXFIRE and FOXFIRE Global) will provide important additional information in this setting [27] and will then trigger a planned combined OS analysis in 2017. Global recruitment was completed in January 2015 and we are awaiting results in the first half of 2017 (www.SIRTEX.com). Moreover, subgroup analysis will also provide insight into the benefit of SIRT for poor prognostic groups like RAS/ RAF mutant patients. This analysis is awaited. There is only one randomised controlled study comparing SIRT and systemic chemotherapy with systemic chemotherapy alone in the treatment of chemotherapy refractory disease [22] (Hendlisz 2010). In this study, progression free survival was doubled (median 2.1 vs 4.5 months) but there was no statistically significant benefit on overall survival (median 7.3 vs 10.0 months). While this is a small single study these survival figures are similar to that seen in a prospective uncontrolled phase II study of SIRT in chemotherapy refractory disease in which median PFS was 3.7 months and median overall survival 12.6 months [17] and in a prospective matched pair analysis in which median PFS was 5.5 months (vs 2.1 months) and median overall survival 8.3 months [28]. Hendlisz 2010 [22] did not show a survival benefit for the addition of SIRT but this may be due to the small numbers in this study and a lack of power to detect a significant difference. This study included patients who were resistant or intolerant to standard chemotherapy (5FU, oxaliplatin and irinotecan) but unfortunately did not collect data on whether patients were truly refractory or how many lines of therapy they had received. While 12 patients
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in this study had previously received an EGFR inhibitor and a further 8 subsequently received an EGFR inhibitor, KRAS testing was not routine and EGFR antagonists were not readily available at the time of the study. Future studies assessing the benefit of SIRT in patients who are refractory to all standard therapy, including biological agents such as bevacizumab and EGFR inhibitors, will become increasingly difficult due to slow recruitment and ongoing development of new agents in the refractory setting such as regorafenib and TAS-102 [28,29]. There is only one randomised controlled study comparing SIRT and regional chemotherapy with regional chemotherapy alone [12] (Gray 2001). The published data reports an improvement in time to progressive disease in the liver with the addition of SIRT (15.9 months vs. 9.7 months, p = 0.001). However, this study did not show any significant improvement in systemic progression or overall survival with the addition of SIRT as first line therapy (median progression free survival 7.3 months vs 5.9 months, p = 0.21). In this review, we separately analysed the outcomes of those patients without extra-hepatic disease (n = 41). There was no statistically significant difference between those receiving SIRT and regional chemotherapy compared with those receiving regional chemotherapy alone however no conclusions can be drawn from this small group. Response rate is an important clinical endpoint in patients with liver metastases, particularly for the small subgroup of patients who may become suitable for liver resection if downstaging can be achieved. The overall response rate with the addition of SIRT to mFOLFOX ± bevacizumab was not significantly different to mFOLFOX ± bevacizumab alone (76.4% vs 68.1%; P = 0.113). In the liver only subset, the overall response rate was significantly improved with the addition of SIRT (78.7% vs 68.8%; P = .042). However, despite the improvement in overall response rate in the liver, the resection rate did not differ with or without SIRT. 36 patients (13.7%) underwent liver resection in the chemotherapy arm compared with 38 patients (14.2%) in the SIRT arm (P = .857). Two studies [20,22] (van Hazel 2004, Hendlisz 2010) combining SIRT with fluoropyrimidine-based chemotherapy also showed improved response rate from 0% to 9.5% in the chemotherapy refractory setting and 0% to 73% in the first line setting but this did not translate into an improvement in overall survival or liver resection rates in either study. It is unclear why the improvement in response rate in the liver has not translated into improved resection rate, whether this reflects reluctance of surgeons to perform hepatic surgery following SIRT, disease distribution or progression of extrahepatic disease. In the palliative treatment of metastatic cancer, toxicity and the impact on quality of life are important endpoints. The addition of SIRT to systemic chemotherapy did result in increased toxicity in the two first line studies [20,21] (Van Hazel 2004, 2016) with higher rates of haematologic toxicities and SIRT related toxicities such as nausea, vomiting, abdominal pain, radiation hepatitis and hepatic failure. The relative high rate of Pgrade 3 adverse events (85.4%) in SIRFLOX study did not result in an improvement in overall PFS. There is a lack of long term follow up of toxicities in this study as the patients were monitored until death or a maximum of 5 years only. There is potential for late radiation effects associated with SIRT such as liver fibrosis [30] and its impact on survival is uncertain. The incidence of delayed toxicity rate was reported in only two phase II studies and three observational studies and ranges from 4 to 10% [17,18,30–32]. Most common delayed toxicities were gastrointestinal ulceration and liver dysfunction. Gastrointestinal ulceration occurs more commonly than liver dysfunction at a rate of 3–4% of grade 1 or 2 toxicities [17]. Liver dysfunction were mainly secondary to grade 3 or 4 radiation induced biliary strictures [18]. However, delayed toxicity rates were only reported in a small number of studies and interpreting whether
grade 3 or 4 liver dysfunction was treatment or disease related is difficult. Quality of life data was only available for two studies [20,12] (Van Hazel 2004, Gray 2001). While SIRT did not appear to adversely affect quality of life in either study, both of these studies assessed quality of life at 3 monthly intervals and are therefore unlikely to have captured the early, likely negative, impact of SIRT on quality of life which needs to be considered when determining its benefit as a palliative treatment. Assessing quality of life immediately following SIRT administration and at one month in future studies may provide more useful data. QOL data for the larger SIRFLOX study has not yet been presented and unfortunately, no quality of life data was collected in the study of chemotherapy refractory disease [22] (Hendlisz 2010) where this is a particularly important endpoint. One prospective phase II study in this setting collected quality of life data [17] and did not show any adverse effect of SIRT on quality of life at 6 weeks. However, only 14 of the 50 patients enrolled in this study completed the questionnaires so these results may be biased. There are a number of other liver directed therapies available for liver dominant metastatic colorectal cancer including radiofrequency ablation (RFA), transarterial chemoembolization (TACE) and stereotactic body radiation therapy (SBRT). The evidence for other liver directed therapies is based predominantly on phase II studies and small randomised trials. The phase II CLOCC study assessed the benefit of RFA. 119 patients were randomised to receive systemic chemotherapy (FOLFOX (±bevacizumab)) in combination with RFA or chemotherapy alone (Ruers et al., 2012) and showed an improvement in PFS rate at 3 years (27.6% vs 10.6%, P = 0.025) [33]. Although this study has demonstrated a survival advantage with the addition of RFA to systemic therapy in the updated results (median survival 45.6 months vs 40.5 months, HR 0.58, 95% CI: 0.38–0.88, P = 0.01) whether RFA alone accounted for the entirety of the observed benefits seen is unclear as patients in the RFA group more often underwent additional resection of selected liver lesions and had better prognostic characteristics compared to the patients in the control group. The final full updated publication is awaited. TACE involves hepatic artery catheterization to cause vessel occlusion with locally delivered chemotherapy. A recent prospective study randomised 74 patients with colorectal metastases who failed oxaliplatin to drug eluting beads loaded with irinotecan (DEBIRI) versus FOLFIRI. The DEBIRI group had significantly improved median survival of 22 months compared to 15 months for the FOLFIRI group (p = 0.031). Toxicities of DEBIRI includes abdominal pain, fever, nausea and liver dysfunction [34]. Stereotactic body radiation therapy (SBRT) allows delivery of highly focused radiation with extreme precision. The local control rates in the liver at 1 and 2 years for SBRT are 67–100% and 55–92%. Overall there is a lack of large randomized studies assessing the benefit of liver directed therapy and to our knowledge, no trials directly comparing different liver directed strategies. Most of the liver directed therapies require specific medical and surgical oncology expertise and should be recommended only in institutions with extensive experience with the procedure. More widespread use of these techniques has been limited by lack of robust data and the need for a high level of expertise in the individual procedures. The combined analysis of the SIRFLOX and FOXFIRE trials will be the largest randomized study of liver directed therapies and we await the final overall survival analysis with interest.
Conclusions There remains a lack of evidence that SIRT improves survival or quality of life in patients with metastatic colorectal cancer,
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whether given alone, or with systemic or regional chemotherapy in first line therapy. The overall survival analysis of the three current first line studies planned for 2017 will hopefully give clinicians guidance as to the role of SIRT in chemo-naive patients. SIRT should therefore continue to be offered to patients within clinical trials in this setting. Results in the chemotherapy pre-treated group are suggestive of a benefit in progression free survival but there is no proven benefit on overall survival. There remains a need to explore the benefit in those truly resistant to chemotherapy and biological agents with a focus on quality of life in this group. Declarations of interest Professor Timothy Price is a member of Advisory Board for Roche, AMGEN, Bayer and Merck. Dr. Christos Karapetis is a member of Advisory Board for Roche, AMGEN and Merck. Dr. Amanda Townsend has received research funding from AMGEN. Acknowledgements Professor Adrian Esterman, Foundation Chair of Biostatistics, University of South Australia, for providing statistical analysis. Michael Tapner, Clinical Research Officer, SIRTEX Technology Pty Ltd, for providing individual patient data from Gray 2001 and Van Hazel 2004. Dr Dainik Patel, The Queen Elizabeth Hospital. Appendix 1 The search strategy given below was used to search MEDLINE (OVID) to February 2016. 1. exp Colorectal Neoplasms/ 2. ((colorect* or colon* or rect* or anal* or anus* or intestin* or bowel*) adj3 (carcinom* or neoplas* or adenocarcinom* or cancer* or tumour* or tumour* or sarcom* or adenom*)).mp. 3. #1 or #2 4. exp Liver Neoplasms/ 5. ((liver or hepatic$ or hepato$) adj3 (carcinom* or neoplas* or cancer* or tumour* or tumour* or metastas$)).mp. 6. #4 or #5 7. Yttrium Radioisotopes/ 8. Microspheres/ 9. (selective internal radi$ or SIRT or radioemboli$ or radioemboli$ or SIR-sphere$ or therasphere$ or ((yttrium$ or $yttrium or 90y$ or radiolabel$) adj5 microsphere$)).mp. 10. (intra-arterial or transarterial or arterial infusion or arterial therap$ or chemoemboli$ or (regional adj3 chemotherap $)).mp. 11. #7 or #8 or #9 or #10 12. #3 and #6 and #11 13. randomized controlled trial.pt. 14. controlled clinical trial.pt. 15. randomized.ab. 16. placebo.ab. 17. clinical trial.sh. 18. randomly.ab. 19. trial.ti. 20. #13 or #14 or #15 or #16 or #17 or #18 or #19 21. humans.sh. 22. #20 and #21 23. #12 and #22
153
The following search strategy was used to search EMBASE (OVID) to February 2016. 1. exp colorectal tumour/ 2. ((colorect* or colon* or rect* or anal* or anus* or intestin* or bowel*) adj3 (carcinom* or neoplas* or adenocarcinom* or cancer* or tumour* or tumour* or sarcom* or adenom*)).mp. 3. #1 or #2 4. exp liver tumour/ 5. exp liver metastasis/ 6. ((liver or hepatic$ or hepato$) adj3 (carcinom* or neoplas* or cancer* or tumour* or tumour* or metastas$)).mp. 7. #4 or #5 or #6 8. exp yttrium/ 9. exp microsphere/ 10. (selective internal radi$ or SIRT or radioemboli$ or radioemboli$ or SIR-sphere$ or therasphere$ or ((yttrium$ or $yttrium or 90y$ or radiolabel$) adj5 microsphere$)).mp. 11. (intra-arterial or transarterial or arterial infusion or arterial therap$ or chemoemboli$ or (regional adj3 chemotherap $)).mp. 12. #8 or #9 or #10 or #11 13. #3 and #7 and #12 14. randomized controlled trial/ 15. randomization/ 16. controlled study/ 17. multicenter study/ 18. phase 3 clinical trial/ 19. phase 4 clinical trial/ 20. double blind procedure/ 21. single blind procedure/ 22. ((singl* or doubl* or trebl* or tripl*) adj (blind* or mask*)).ti, ab. 23. (random* or cross* over* or factorial* or placebo* or volunteer*).ti,ab. 24. #19 or #16 or #20 or #22 or #15 or #21 or #17 or #14 or #23 or #18 25. ‘‘human*”.ti,ab. 26. (animal* or nonhuman*).ti,ab. 27. #26 and #25 28. #26 not #27 29. #24 not #28 30. #13 and #29
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