COLLISION trial - Colorectal liver metastases: surgery versus thermal ablation - a phase III prospective randomized controlled trial

Colorectal carcinoma is one of the most common malignancies in the Western
world. In the course of the disease 40-60% of patients develop colorectal liver
metastases (CRLM). Without treatment survival for these patients is cumbersome
with a median overall survival (OS) of 7.4 - 11 months. Surgical resection
represents the historical standard and treatment of first choice with 5-year OS
reaching 35-60%. To eliminate unresectable metastases, several ablative
strategies have emerged. Thermal ablation techniques employing radiofrequency
ablation (RFA) and microwave ablation (MWA) have slowly worked their way into
common clinical practice and international guidelines. Thermal ablation for
small liver lesions has an excellent safety profile with a low complication
rate for smaller liver tumors. However, the issue of local site recurrence
after thermal ablation has prohibited widespread adoption of the technique for
resectable lesions. In the last few years, thermal ablation techniques have
substantially improved with primary efficacy rates (complete ablation after the
first procedure) for lesions <=3cm now reaching 92-100%. These results are
comparable to recurrences after surgical resection for similar-sized lesions.
The relative ease to percutaneously re-ablate potential site recurrences,
nowadays often in the setting of a one-day admission under conscious sedation,
has downgraded the relevance of LSR with local control rates (assisted
technique effectiveness) approaching 100% for lesions <=3cm. The recently
presented long-term results from the EORTC CLOCC-trial (ASCO 2015) show a clear
survival benefit of RFA plus systemic chemotherapy over chemotherapy alone for
unresectable CRLM: 8-year OS 36% vs 8.9% (p=0.01; HR 0.58; 95%CI 0.38-0.88).
Numerous studies have demonstrated a superior safety profile in addition to
lower direct and indirect costs of thermal ablation over surgical resection.
Despite this, the 5-year OS (range 15-62%) of thermal ablation for patients
with unresectable CRLM has been labelled inferior to surgical resection for
patients with resectable CRLM according to previous meta-analyses and
systematic reviews. Because the groups are by definition confounded by
indication these results should be interpreted with care. The apparent
selection bias, when comparing patients with unresectable disease to surgical
candidates, the superior safety profile, and the competitive overall survival
results for the more recent reports, mandate the setup of a randomized
controlled trial. We have designed a two-arm phase-III randomized controlled
trial comparing surgical resection (standard of care) to thermal ablation
(experimental arm) for resectable and ablatable CRLM <=3cm.

The primary objective is to prove non-inferiority of thermal ablation compared
to hepatic resection in patients with at least one resectable and ablatable
CRLM (<=3cm) and no extrahepatic disease.

COLLISION is a prospective multi-center phase-III randomized controlled trial.
We hypothesize that thermal ablation is non-inferior to surgery for the
selected patient groups in terms of the primary objective (overall survival).
The Cox proportional hazards model (1-sided; non-inferiority or superiority) is
used for sample size calculations. Given the superior safety profile we
consider a hazard ratio of 1.3 to represent the upper limit of non-inferiority
(non-inferiority margin). An HR of 1.3 corresponds to a 56.5% chance of the
ablated patients to die first ((P = HR/(1 + HR) = 1.3/(1 + 1.3) = 0.565
(56.5%)). With 3 years of patient accrual and five years of follow-up we will
have reached 60% of events (death) in approximately 6.5 years (overall
probability of event, pE =0.6). The calculated sample size therefore is 599
(NS).To account for a 10% drop-out ratio (NDO=69) prior to randomization and a
3% loss to follow-up (NLTFU=18) after randomization we need to include 687
patients (NI). A total number of 618 patients will be randomized (NR) into one
of two arms: arm A will undergo surgical resection (n=309) and arm B thermal
ablation (n=309) for appointed target lesions.

Eligible patients will be stratified into low-, intermediate- and high disease
burden after assessment by an expert panel. The panel, consisting of at least
two diagnostic radiologists, two interventional radiologists and two
hepatobiliary and/or oncological surgeons, will appoint lesions that are
resectable and ablatable as target lesions, resectable and unablatable lesions
as unablatable lesions and ablatable but unresectable lesions as unresectable
lesions. All unablatable lesions should be resectable and all unresectable
lesions should be <=3cm and ablatable.

Low disease burden: 1-3 CRLM <=3cm, no unablatable or unresectable lesion(s).
Intermediate disease burden: >=1 target lesion(s), and >=1 unablatable lesion(s)
requiring minor surgery or unresectable lesion(s) requiring ablation(s).
High disease burden: >=1 target lesion(s), and >=1 unablatable lesion(s)
requiring major surgery (trisegmentectomy, (extended) hemihepatectomy).

Eligibility needs to be reconfirmed during the surgical procedure. Hereafter
patients will be randomized to undergo surgical resection of the target lesions
(allowing thermal ablation for additional unresectable lesions) or thermal
ablation (allowing resection for additional unablatable lesions).
Postprocedural care will be identical between the two groups with the exemption
that hepatic recurrences (either local site recurrence or new lesions) suitable
for both resection and ablation will again be treated with the technique used
to treat the initial target lesion(s). Conferring to national guidelines
follow-up will include imaging, laboratory tests including tumor markers (CEA)
and quality of life questionnaires. Since every local center uses different
imaging techniques, the method of imaging is chosen by local expertise.
Patients with recurrences that are considered unsuitable for additional focal
therapy will be re-referred to their medical oncologist to assess additional
systemic chemotherapy. In the event of chemotherapeutic down-staging hereafter,
focal therapy can be reconsidered.

Reported outcomes after thermal ablation for CRLM are improving. Survival
results after thermal ablation for non-surgical candidates have approached the
results achievable with surgery for resectable disease. The superior safety
profile and the suggested lower overall costs of thermal ablation over surgical
resection, stress the need to conduct a randomized controlled trial for
patients with small resectable and ablatable CRLM. By participating in the
study, patients agree to either undergo standard treatment for hepatic
metastases by means of hepatic resection, or to undergo the method studied
which is open thermal ablation of the metastases. For each participant, the
method of treatment will be decided upon by randomization. Pre-operative
screening will not be different from the standard treatment and will not be an
extra burden. If participants will receive treatment with thermal ablation, we
anticipate less peri-operative complications and hence a shorter hospital stay.
Follow-up after the procedure will be identical to standard treatment. If our
hypothesis will prove to be wrong, patients having undergone thermal ablation
are at risk of having a shorter overall survival, shorter disease-free
survival, and higher local recurrence rate, leading to a lower quality of life.
If thermal ablation proves to be indeed non-inferior to surgical resection in
this patient group, patients having undergone ablation will have had a less
invasive procedure with presumably shorter hospital stay and fewer
postoperative complications, with comparable overall survival. In a broader
sense, if our hypothesis will prove right, a switch in treatment-method for the
group studied will lead to a lowering in overall post-procedural morbidity and
mortality and length of hospital stay. Moreover, this will likely lead to
improved quality of life. Subsequently, a cost-benefit analysis may prove
beneficial for treatment with thermal ablation with respect to overall hospital
and treatment costs given the well-known direct and indirect costs of both
procedures.