BARCELONA, SPAIN, 1 July 2017 - For patients with colorectal cancer that has metastasised to the liver, having a primary tumour on the left side, as opposed to the right side of the colon, is known to be a significant advantage in terms of treatment response.
But now a new study, presented here at the ESMO 19th World Congress on Gastrointestinal Cancer, suggests this imbalance may be at least partially redressed.
Reversing the usual pattern, patients whose liver metastases had spread from right-sided primary tumours (RSP) had a 36% better survival rate after treatment with a combination of first-line chemotherapy and selective internal radiation therapy (SIRT) using Y-90 resin microspheres, compared to chemotherapy alone, according to the study.
This same treatment combination was no better than chemotherapy only in patients with left-sided primary tumours (LSP).
“These findings are good news for patients with right-sided primary tumours, who have a much worse prognosis and fewer treatment options than patients with left-sided tumours,” said study investigator Guy van Hazel, MD, from the University of Western Australia in Perth, Australia.
“We are excited because hitherto no treatment apart from the addition of bevacizumab to chemotherapy has improved the dismal outcome of liver metastases coming from right-sided primary tumours.”
The analysis included 739 patients from two completed studies called SIRFLOX (SF) and FOXFIRE-Global (FFG).
All patients had liver-only or liver-dominant metastatic colorectal cancer (mCRC), and had been randomised to receive either standard chemotherapy alone, or combined with SIRT. The chemotherapy regimen was mFOLFOX6, and most patients received bevacizumab as well.
Information on the patients’ primary tumour location was recorded at the start, with 24% having right-sided and 73% left-sided disease (the remaining 3% had primary tumours on both sides of the colon, or the primary tumour site was unknown).
Overall, outcomes were not different between the chemotherapy alone and chemotherapy plus SIRT groups, with median overall survival (OS) and progression-free survival (PFS) around 24 months and 11 months, respectively.
However, when the investigators examined patients with RSP and LSP separately they saw a clear difference.
Patients with liver metastases from RSP had significantly better OS when SIRT was added to their chemotherapy compared to those who had chemotherapy alone (22.0 vs. 17.1 months, respectively; p=0.007; Hazard Ratio [HR]: 0.64 [95% CI: 0.46-0.89]), but this was not the case for patients with LSP (24.6 vs. 25.6 months; p=0.279; HR: 1.12 [0.92-1.36]).
“That means that RSP patients treated with chemotherapy plus SIRT have a 36% reduced risk of dying at any time point,” said van Hazel.
There was also a 27% improvement in PFS, although this was not statistically significant.
“This is the first time that location of primary tumour has been linked to radiation therapy,” said van Hazel, and although it’s possible that it may only apply to patients receiving first-line therapy, he said it opens a new treatment option for these patients.
There were no differences in side effects between patients with RSP and LSP tumours, and although patients who had both chemotherapy and SIRT did experience more side-effects than those who had chemotherapy alone, these were “predictable and manageable,” said van Hazel.
Commenting on the study, ESMO spokespersons Dirk Arnold, from Instituto CUF de Oncologia in Lisbon, Portugal and Eric Van Cutsem, University Hospitals Leuven, Belgium, said that these findings contribute to the recent debates on both the biological heterogeneity of colon cancers and tumour localisation.
“It remains to be confirmed whether these results mean that right-sided tumours are more sensitive to this kind of radiotherapy – or whether this is simply related to the fact that the molecular characteristics of right-sided tumours allow less treatment options, because they have more mutations,” they explained. “Additionally the well-known worse prognosis of right-sided tumours increases the relative importance of a non-systemic treatment option. More data on the molecular factors determining these results are warranted.”
Notes to Editors
- Abstract LBA-006 – ‘Impact of primary tumour location on survival in patients with metastatic colorectal cancer receiving selective internal radiation therapy and chemotherapy as first-line therapy’ will be presented by Dr Van Hazel Guy during ‘Session XIX: Colorectal Cancer’ on Saturday, 01 July, 12:30 to 12:55 (CEST) in Auditorium A.
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Abstract for LBA-006
Impact of primary tumour location on survival in patients with metastatic colorectal cancer receiving selective internal radiation therapy and chemotherapy as first-line therapy
van Hazel Guy 1, Heinemann Volker 2, Sharma Navesh 3, Taieb Julien 4, Ricke Jens 5, Peeters Marc6, Findlay Michael7, Gibbs Peter8, SIRFLOX and FOXFIRE-Global trial investigators
1University of Western Australia, Perth, Western Australia, Australia, 2Ludwig-Maximilian-University of Munich, Germany; 3University of Maryland Medical Center, Baltimore, Maryland, USA; 4Paris Descartes University, Georges Pompidou European Hospital, Paris, France; 5University Clinic Magdeburg, Magdeburg, Germany; 6Antwerp University Hospital, Antwerp, Belgium; 7Cancer Trials New Zealand, Auckland, New Zealand; 8Western Hospital, Footscray, Victoria, Australia.
Background: Primary tumour location of metastatic colorectal cancer(mCRC)is emerging as a major prognostic factor and predictor of response to some treatments, with right-sided primary tumours (RSP) having inferior prognosis and response. The impact of primary tumour side on outcomes after selective internal radiation therapy (SIRT) of patients with mCRC liver metastases has not previously been examined, but a survival benefit in patients with RSP was recently reported in an exploratory analysis of the FOXFIRE studies(Sharma RA et al. 2017 ASCO Annual Meeting; J Clin Oncol 2017;35(Suppl):Abs 3507). Therefore, we analysed data from the SIRFLOX (SF) and FOXFIRE-Global (FFG) trial cohorts to assess the impact of primary tumour location on survival and other outcomes.
Methods: The SF and FFG studies were designed with similar protocols. Patients with previously untreated liver-only or liver-dominant mCRC were randomised (1:1) to receive mFOLFOX6 chemotherapy alone or with a single administration of SIRT using yttrium-90 resin (Y-90) microspheres (SIR-Spheres; Sirtex, North Sydney). Patients could receive bevacizumab at investigator discretion. Primary tumour location was captured prospectively in the case report form. RSP was defined as any primary tumour that was proximal to the splenic flexure; left-sided primary tumour (LSP) included a primary tumour at the splenic flexure, the more distal colon and the rectum. Progression-free survival (PFS) and overall survival (OS) data were examined with a focus on the influence of tumour side on outcomes.
Results: Of the 739 patients recruited (SF n=530; FFG n=209), 179 (24.2%) had a RSP and 540 (73.1%) had a LSP. In the combined analysis of all 739 patients, the addition of SIRT to mFOLFOX6 chemotherapy had no impact on median PFS or OS [11.1 vs. 10.6 months (p=0.22); 24.3 vs. 24.6 months (p=0.84) with SIRT or without SIRT, respectively]. For patients with a RSP, OS was significantly improved with the addition of SIRT [22.0 vs. 17.1 months, respectively; p=0.007; Hazard Ratio (HR): 0.64 (95% CI: 0.46-0.89)], but not for patients with a LSP [24.6 vs. 25.6 months; p=0.279; HR: 1.12 (0.92-1.36)]. The location by treatment interaction was highly significant [Chi-square: 9.49; p=0.002; HR: 0.548 (0.37-0.80)]. For patients with a RSP, the trend was for improved PFS with the addition of SIRT (10.8 vs. 8.7 months; p=0.053; HR: 0.73 (0.53-1.01)], but not for patients with a LSP [11.4 vs. 10.8 months; p=0.426; HR: 0.93 (0.78-1.11)]. The incidence of grade ≥3 adverse events did not differ for RSP and LSP (p>0.05).
Conclusions: In the SF and FFG studies, the addition of SIRT using Y-90 resin microspheres to first-line mFOLFOX6 chemotherapy was associated with a statistically and clinically significant gain in OS for patients with a RSP but not in patients with a LSP. These findings are being validated in the remaining FOXFIRE trial cohort. These data add to the growing literature describing primary tumour location-based differences in mCRC outcomes with some treatments, and may support a side-based approach to treatment selection including SIRT. The biological drivers of these differences remain to be defined.