COLDFIRE 2: IRE is safe, effective in patients unsuitable for thermal ablation or surgery

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COLDFIRE
Martijn Meijerink

Irreversible electroporation (IRE) is an effective and relatively safe treatment for colorectal liver metastases 5cm or smaller that are deemed unsuitable for partial hepatectomy, thermal ablation, or further systemic therapy, results of the COLDFIRE-2 study, published in Radiology, report. The two-centre, prospective, single-arm, Phase II clinical trial was conducted by Martijn Meijerink, Alette Ruarus (both Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands) and colleagues.

IRE is a non-thermal ablative technique that uses high-voltage electrical pulses, and, according to the study authors, has shown promise for eradicating tumours near critical structures, including blood vessels and bile ducts. This is exactly why it presents an attractive treatment option to many interventionalists: those patients treated in COLDFIRE-2 were all inappropriate candidates for partial hepatectomy or thermal ablation due to the proximity of their tumours to critical structures. Indeed, up to 70% of patients with colorectal liver metastases are not eligible for surgery because of comorbidities or owing to the number, location, or distribution of the metastases.

Meijerink, Ruarus et al explain that, although most current guidelines consider thermal ablation (radiofrequency and microwave; RFA and MWA) to be the standard of care for small, unresectable colorectal liver metastases, its contraindication for tumours close to large hepatic vessels presents an unmet clinical need that can be catered for by IRE.

The COLDFIRE-1 study (Colorectal liver metastases disease: efficacy of irreversible electroporation, a single-arm, Phase 1 clinical trial) first demonstrated IRE’s ability to eradicate colorectal liver metastases in humans. The COLDFIRE-2 triallists write: “The reported efficacy of hepatic IRE varies widely (45.5–100%) because of the heterogeneity of patient and tumour characteristics, and most studies represent small retrospective cohort studies or case reports with short-term follow-up. The early adaptation of electroporation into the toolbox of ablative methods by the European Society for Medical Oncology in 2016 seems premature given the nonexistence of larger-scale prospective controlled efficacy studies.”

Between June 2014 and November 2018, 50 participants, with 76 fluorine 18 (18F) fluorodeoxyglucose (FDG) PET-avid colorectal liver metastases 5cm or smaller between them, underwent percutaneous or open IRE. Follow-up included tumour marker assessment and 18F-FDG PET/CT imaging every three months for the first year after IRE, and every six months thereafter. The median follow-up after the first, second, and third IRE procedures was 23.9 months, 9.5 months, and 6.3 months, respectively.

The study mets its primary endpoint, which mandated that at least 50% of treated participants had to be alive without local tumour progression at 12 months, defined as local tumour progression-free survival. Per-participant one-year local tumour progression-free survival was 68% (95% confidence interval [CI]: 59, 84) according to competing risk analysis.

Outlining why this primary endpoint measure was used, Meijerink, Ruarus and colleagues explain: “Because the participants in this trial were often heavily pre-treated, overall survival would not properly reflect the efficacy of IRE, and therefore one-year local tumour progression-free survival was chosen as the primary end point.”

The authors go on to say that these results “are in line with those of recent retrospective series”, and conclude: “Thus, we believe that IRE should be accepted as a niche indication for difficult-to-reach colorectal liver metastases, but only in the salvage setting of permanent unresectability and unsuitability for thermal ablation.”

Writing in an accompanying editorial in Radiology, S Nahum Goldberg (Hadassah Hebrew University Medical Center, Jerusalem, Israel) claims the COLDFIRE-2 trial “has the potential to provide a substantial impact on the treatment of this malady and on interventional oncology as a whole”.

Speaking of the trial, he says: “This well-designed and superbly executed effort represents a pivotal clinical trial of IRE for the treatment of intrahepatic colorectal metastases unsuitable for partial hepatectomy, thermal ablation, and further systemic treatments. The authors offer hope for achieving successful treatment for a larger population of difficult-to-treat patients—namely those with centrally located tumours and those with tumours between 3 and 5cm in diameter.”

He continues: “Although the populations were relatively small and will require further confirmation, these data suggest that IRE techniques may enable adequate coverage to expand the range of successfully treated tumours. Some of these benefits may be due to synergistic effects between IRE and the chemotherapy administered in a majority of patients. Combination therapy between thermal ablation and induction chemotherapy—administered systemically or by means of chemoembolization—has demonstrated results that can even outperform surgery.

“Further research and collective experience are warranted if we are to achieve the best clinical results possible. […] The final results of COLDFIRE-2 have been long anticipated and are of great interest to interventional, medical, and surgical oncologists and the patients we serve.”

Secondary endpoints: IRE effective, but depends on operator experience

Secondary aims included safety, technical success, local control allowing for repeat procedures, disease-free status, and overall survival.

The per-tumour one-year local tumour progression-free survival rate was 79% (95% CI: 68%, 88%). Median distant progression-free survival was 5.3 months (95% CI: 2.5, 8.1). The most frequent site of first recurrence was the liver; median extrahepatic progression-free survival was 12.5 months (95% CI: 5.9, 19.1). Median overall survival from was 2.7 years (95% CI: 1.6, 3.8) from the first IRE and 4.8 years (95% CI: 3.1, 6.6) from the date of resection of the primary tumour.

The study authors detail that after repeat procedures, local tumour control was achieved in 74% of participants (37 of 50 patients). They expand: “Six participants were considered unsuitable for local repeat treatment at first local tumour progression because of coexisting distant disease progression, making local treatment futile”.

Local control was not achieved in two participants despite multiple attempts to eradicate the tumours. Recurrences were treated with repeat IRE (n=12), thermal ablation (n=three), stereotactic body radiation therapy (n=three), or selective internal radiation therapy (n=one). In a comparison of the first five versus the next 45 participants, the eventual local tumour progression rate was 80% (four of five) versus 33% (15 of 45) (p=0.06).

Meijerink, Ruarus, and colleagues state that, although this did not reach statistical significance in their study, “the local tumour progression rate of 80% versus 33% in the first five versus the next 45 participants strongly suggests that IRE is dependent on operator experience.”

They determine that, in their opinion, this “underlines the necessity to set up dedicated training programmes and preferably claim minimum volume thresholds” for performing IRE.

Cox regression analysis showed no statistically significant difference in local tumour progression-free survival between small and medium-size tumours (hazard ratio, 1.7; p=0.22). Therefore, Meijerink, Ruarus, et al speculate that technique efficacy may be less susceptible to size with IRE, in which tumours are bracketed by the electrodes, compared with single-probe thermal ablation.

The overall complication rate was 40%: 23 participants experienced a total of 34 adverse events in 25 of the 62 procedures. The most common grade 3 adverse events were de novo biliary obstructions (n=3), periprocedural cardiac arrhythmias (n=4), and portal vein thrombosis (n=3). Two participants experienced a grade 4 adverse event. One participant (2%), who an an infected bilioma after IRE, died fewer than 90 days after the procedure—classified as a grade 5 event. “Our higher complication rate can be partially explained by our prospective study design and allowance for simultaneous procedures during IRE. […] Therefore, not all reported adverse events are likely to be related to the IRE procedure itself,” Meijerink, Ruarus, and co-authors write.


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