Having a think about the available data on liver-directed...

Having a think about the available data on liver-directed therapy first line for mCRC and implications for upcoming FOXFIRE results, and I think there is good reason to be positive about the outcomes, at least for the subgroup with metastases confined to the liver at diagnosis.  Has been discussed before, but hope this is useful.  The attached image is from the SIRFLOX study paper, and shows overall PFS data broken down into subgroups.  The paper also included a breakdown of liver-PFS which was significantly better with SIRT as we already know.

Looking at the subgroup data, it seems that small burden tumours (<25% liver burden, 377/530 cases) nearly achieved a significant benefit with SIRT, it is certainly trending the right way.  Also, overall PFS for patients with liver only tumours (318/530 cases) is trending towards a benefit with SIRT compared with cases having known extra hepatic disease (makes sense).  Presumably if you selected the small burden liver-only cases then there would be a good chance of a significant difference in overall PFS in that subset.  Having the primary out would also be nice.  

My point is that there is a very good chance that a well defined (and reasonably sized) subgroup MAY WELL HAVE A SIGNIFICANT OVERALL PFS BENEFIT in SIRFLOX.  

I have taken another look at the CLOCC study data, which may give some clue regarding the implications of successful liver metastasis treatment for mCRC.  The CLOCC study used a liver-targeted therapy (radiofrequency ablation) with FOLFOX-based systemic chemotherapy in patients with unresectable mCRC confined to the liver, showed that control of hepatic metastases can translate to a substantial impact on OS.  In the CLOCC study patients with extrahepatic disease were excluded and ALL patients had their primary tumour resected (vs ~45% with residual primary tumour in SIRFLOX, not sure if primary tumours were allowed for FOXFIRE?).

The CLOCC study demonstrated a 7 month median improvement in PFS at any site (HR, 0.57; 95% CI 0.38 to 0.85; P = .005), SIMILAR in extent to the liver-PFS benefit in SIRFLOX.  A comparable overall PFS result might have been possible in SIRFLOX if selection criteria had been more stringent.  In CLOCC there was a significant difference in OS in favour of the RFA+CT arm (HR = 0.58, 95% CI: 0.38-0.88, p = 0.01). Observed median OS was 45.6 months (95% CI: 30.3 – 67.8) in the RFA+CT arm vs. 40.5 months (95% CI: 27.5 - 47.7) in the CT arm.  

7 month overall PFS benefit translated to a 5 month OS gain.

In CLOCC, the liver, either alone or in combination with extrahepatic disease, was the first site of progressive disease in 27 patients in the combined treatment group (45%) compared with 45 patients in the systemic treatment alone group (76.3%) (P < 0.0001; supplemental Figure S1, available at Annals of Oncology online). In total, on 56 patients treated with RFA, 9 patients (16.1%) had local recurrence at the RFA site at first progression.

In SIRFLOX, the liver was first site of progression (+/- other site) in 92% on chemo-only patients vs 72% in the SIRT arm.  No breakdown of liver-only subset available, but there is a parallel with the CLOCC study in that a liver directed therapy made first progression in the liver less likely.  Similarly, the treated liver lesion was also less likely to be the site of progression, affecting 87% of cases in the chemo-only group vs 58% of the SIRT treated group.

Will get an answer in a few months, but hopefully between the three trials there will be sufficient cases to analyse the liver-only subgroup.  Having such a high proportion of cases with primary in situ was a mistake in trial design IMO.  However, if the data for SIRT first line looks promising this might warrant a change of practice to remove the primary in liver only cases and remove a source of mets.  If it buys another 8 months, well worth it.


http://meetinglibrary.asco.org/content/151361-156