Ablation with Confirmation of Colorectal Liver Metastases (ACCLAIM) Prospective Trial for Microwave Ablation as a Local Cure

• Principal Investigator: Constantinos T. Sofocleous, MD, PhD, FSIR, FCIRSE, Memorial Sloan Kettering Cancer Center
• Site locations approved and activated for enrollment include Mayo Clinic, The University of Texas MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, and Baptist Health Miami Cancer Institute (pending approval)

ACCLAIM Institution Sites:

Synopsis:

In this prospective multi-center trial we propose to establish microwave ablation (MWA) as the preferred curative therapy for selected colorectal liver metastases (CLM) that can be ablated with sufficient margins. Our hypothesis is that MWA of CLM ≤ 2.5 cm with confirmation of ablation margin over 5 mm achieves definitive local tumor control (local cure) with minimal morbidity.

This international study will enroll subjects with one to three CLMs (for a total of 330 tumors/approximately 275 subjects) eligible for local cure using MWA. Any FDA cleared or CE Marked MWA device will be acceptable for use. MWA will be performed with the intent to create a minimum margin of ablation of 5.0 mm and ideally ≥10 mm from the edge of the target tumor to the ablation periphery. Minimum margin (MM) size will be assessed immediately after MWA (intra-procedurally) using an FDA approved/cleared image-processing software to provide 3D assessment of the ablation zone and margin. During this trial, a minimal ablation margin of 5.0 mm will represent the necessary condition for technical success of the ablation. Ablation assessment of the MM will be reviewed by an independent core lab within 7 days and within 4-8 weeks after the MWA.

For MMs less than 5 mm, repeat MWA will be performed whenever feasible, within 30 days (and 60 days from initial MWA) from detection, in order to achieve sufficient MM (> 5mm). Minimum margin size will be correlated with time to local tumor progression. Local disease-free progression (within or abutting the ablation zone) and hepatic disease-free survival (accounting for all tumors ablated) stratified by MM of ≥ 5.0-9.9 mm and ≥ 10.0 mm will be assessed.

Background:

Despite a very favorable safety profile and a curative potential, the relatively high local tumor progression (LTP) rates after thermal ablation (TA) when compared to surgery historically, have limited the widespread use of this treatment in patients with metastatic colorectal disease to the liver. Regardless of tumor modality, treatment failure and local tumor progression (LTP) have been attributed to insufficient coverage of the tumor by the ablation zone (tumor and margins).

Hypothesis:

To demonstrate that microwave ablation (MWA) of up to 3 hepatic metastases, each with a maximum diameter of ≤ 2.5 cm will result in a 2-year local progression free survival of at least 90%.

Study Design:

Open-label multicenter trial with sites in the United States and Europe. 

Primary Endpoint:

To estimate local disease-free survival (within or abutting the ablation zone) of colorectal liver metastases treated with MWA with ablation margin confirmation.

Secondary Endpoints:

1. Hepatic progression free survival by Kaplan-Meier estimate
2. Local tumor progression free survival between sufficient (5.0-9.9 mm) and ideal (≥10 mm) ablation margin categories using Kaplan-Meier methodology and the log-rank test
3. Progression free survival using Kaplan-Meier methodology and the log-rank test
4. Overall and disease specific survival following MWA using Kaplan-Meier methodology
5. Proportion of target tumors treated with an ablation zone (AZ) that completely covers the target tumor(s) with minimal margin (MM) of at least 5 mm
6. Proportion of subjects with CTCAE grade 3 events or greater within 90 days after MWA

Industry Support:

This study is supported by grants funded by the following industry partners:

Study Rationale:

More than one million people worldwide are affected by colorectal cancer, with approximately 50% of this population developing liver metastases at some point during the course of the disease¹.

Curative-intent surgery for colorectal liver metastases:

Complete extirpation of liver metastases from colorectal cancer can result in cure. The reference standard is surgical resection. Among a series of 1600 resections at a single institution²  (of which 7% were R1 resections), the median recurrence-free survival (RFS) was 23 months, RFS rate  was 38% at 3 years and 33% at 5 years. Major morbidity occurred in 20% of cases, with 1% mortality. Positive margins, extrahepatic disease, and high Clinical Risk Score were predictors of worse disease-specific survival. Among 1669 resections from a multi-institutional database³ including ablation in 10% of cases, median RFS was around 26 months. For patients with recurrence, median time to recurrence was 15 months. Disease-free survival (DFS) was 24% at three years and 15% at five years; 34% of patients recurred in the liver only, 18% extra-hepatic only, and 14% in both. Operative mortality was 1.6 %. Patients with hepatic recurrence can be treated with repeated resection^4,5 or thermal ablation^6-8.

Ablative therapy for colorectal liver metastases:

Image-guided therapies have been used as an alternative local treatment with curative potential while avoiding the morbidity and mortality of surgery. In addition, certain ablation techniques may be feasible in anatomic areas where surgery is not.

Thermal ablation (TA) techniques use electromagnetic energy delivered directly in the tumor via special needles/electrodes, in order to achieve cytotoxic levels of thermal energy and destroy tumors in situ¹³. Image-guided TA has been increasingly used in the treatment of relatively small colorectal liver metastases (CLM). TA modalities include radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation.

A study¹⁴ comparing resection, resection plus intraoperative radiofrequency ablation, and intraoperative ablation alone showed that rates of hepatic recurrences were similar in the three groups, either for new lesions or recurrences of treated lesions.  The choice of therapy was made on the basis of size and topography of the tumor with the goal of achieving R0 treatment .The expected survivals at 2 years were similar in the 3 groups: 75% (RFA alone), 68% (RFA + resection), and 83% (resection alone) (P = 0.763).  Other studies^15,16 comparing resection with RFA for treatment of solitary colorectal liver metastases had comparable results. Median survival was 41 month after resection and 37 months after RFA, with a 3-year survival rate of 55% and 53%, respectively in the study by Oshowo et al.¹⁵ Hur et al.¹⁶ also found 5-year PFS of  95.7% versus 85.6%,  and 5-year OS of 56% and 55%, for resection and ablation, respectively.

References:

1. Siegel RL, Miller KD, Fedewa SA, et Colorectal cancer statistics, 2017.  CA Cancer J Clin. 2017; 67(3):177-193.

2. House MG, Ito H, Gonen M, et Survival after hepatic resection for metastatic colorectal cancer: trends in outcomes for 1,600 patients during two decades at a single institution. J Am Coll Surg. 2010;210(5):744-752,  752-745.
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5. Wanebo HJ, Chu QD, Avradopoulos KA, Vezeridis Current perspectives on repeat hepatic resection for colorectal carcinoma: a review. Surgery. 1996;119(4):361-371.
6. Sofocleous CT, Petre EN, Gonen M, et CT-guided radiofrequency ablation as a salvage treatment of colorectal cancer hepatic metastases developing after hepatectomy. J Vasc Interv Radiol. 2011;22(6):755-761.
7. Elias D, De Baere T, Smayra T, Ouellet JF, Roche A, Lasser Percutaneous radiofrequency thermoablation as an alternative to surgery for treatment of liver tumour recurrence after hepatectomy. Br J Surg. 2002;89(6):752-756.
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11. Laurent C, Sa Cunha A, Couderc P, Rullier E, Saric Influence of postoperative morbidity on long-term survival following liver resection for colorectal metastases. Br J Surg. 2003;90(9):1131-1136.
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13. Vogl TJ, Farshid P, Naguib NN, et Thermal ablation of liver metastases from colorectal cancer: radiofrequency, microwave and laser ablation therapies. Radiol Med. 2014;119(7):451- 461.
14. Leblanc F, Fonck M, Brunet R, Becouarn Y, Mathoulin-Pelissier S, Evrard S. Comparison of hepatic recurrences after resection or intraoperative radiofrequency ablation indicated by size and topographical  characteristics of the   Eur J Surg Oncol. 2008;34(2):185-190.
15. Oshowo A, Gillams A, Harrison E, Lees WR, Taylor Comparison of resection and radiofrequency ablation for treatment of solitary colorectal liver metastases. Br J Surg. 2003;90(10):1240-1243.
16. Hur H, Ko YT, Min BS, et Comparative study of resection and radiofrequency ablation in the treatment of solitary colorectal liver metastases. Am J Surg.  2009;197(6):728-736.