COLLISION RELAPSE trial - Recurrent colorectal liver metastases: repeat local treatment +/- neoadjuvant systemic therapy - a phase III prospective randomized controlled trial

Colorectal cancer (CRC) has a high incidence and mortality rate worldwide. The
prognosis of CRC patients is largely dependent on the presence of distant
metastases, most frequently involving the liver. Up to 50% of patients develop
colorectal liver metastases (CRLM) at some time during the course of treatment.
If left untreated five-year overall survival (OS) is <3% and when treated with
palliative chemotherapy five-year OS improves to approximately 11%. One-fifth
of CRLM patients are eligible for local treatment with curative intent. This
approach for upfront resectable and/or ablatable disease reaches 5-year OS of
44-58%. If CRLM are initially unresectable and unablatable, 5-year OS up to 33%
is reached, when CRLM are successfully downstaged with induction chemotherapy.
Two randomized controlled trials (EORTC 40983, Nordlinger et al. and JCOG 0603,
Kanemitsu et al.) showed that routine use of (neo)adjuvant chemotherapy for
resectable and/or ablatable disease does not lead to improved OS. Therefore
perioperative and adjuvant treatment is no longer recommended for resectable
and/or ablatable CRLM.
After initial treatment of CRLM, new intrahepatic recurrence develops in
64%-85% of patients. To treat recurrent CRLM partial hepatectomy or thermal
ablation is considered standard of care. With upfront repeat local treatment
5-year reaches 51%. Given the poorer prognosis associated with patients with
recurrent disease, attributed to presumed worse tumor biology and the presence
of intrahepatic micrometastases, neoadjuvant chemotherapy prior to repeat local
treatment has been suggested to prolong survival and to select responders who
will benefit from local treatment.
Our recent pooled meta-analysis (Dijkstra et al.) reported no difference in OS
between neoadjuvant chemotherapy followed by repeat local treatment and upfront
repeat local treatment. However, the included retrospective comparative series
showed a trend towards improved survival for the addition of neoadjuvant
chemotherapy to repeat local treatment. Furthermore, the largest to date
registry study (LiverMetSurvey) advocates neoadjuvant chemotherapy followed by
repeat local treatment to adequately select good candidates and to control
rapidly progressive disease based on an OS benefit favoring the use of
neoadjuvant chemotherapy before repeat local treatment: 5-year OS: 61.5% vs.
43.7% (HR = 0.529; 95%CI 0.299-0.934).
Although the recommendation of neoadjuvant chemotherapy followed by repeat
local treatment is frequently reported, the exact role of neoadjuvant
chemotherapy prior to repeat local treatment in case of recurrent and locally
treatable CRLM remains uncertain.
The negative results from the EORTC 40983 and JCOG 0603 trials for
(neo)adjuvant chemotherapy prior to the initial local treatment and the absence
of prospective randomized controlled studies for recurrent disease makes us
question the benefit of adding neoadjuvant chemotherapy to repeat local
treatment. Furthermore, the well-known risks associated with liver surgery
following repeated cycles of oxaliplatinum (sinusoidal obstruction syndrome)
and 5-fluorouracil or irinotecan (liver steatosis) and the systemic toxicity,
side-effects, reduced quality of life (QoL) and added direct costs should be
considered.
To assess the added value of neoadjuvant chemotherapy we have designed a phase
III randomized controlled trial (RCT) directly comparing upfront repeat local
treatment (control) with neoadjuvant systemic therapy followed by repeat local
treatment (intervention).

This study has been transitioned to CTIS with ID 2024-515341-41-01 check the CTIS register for the current data.

The primary objective is to demonstrate superiority of neoadjuvant systemic
therapy followed by repeat local treatment as compared to upfront repeat local
treatment in patients with at least one locally treatable recurrent CRLM in the
absence of extrahepatic disease.

The COLLISION RELAPSE trial is a prospective multicenter phase III randomized
controlled trial. The primary conducting center will be the Amsterdam UMC
(Amsterdam, the Netherlands). We hypothesize that neoadjuvant systemic therapy
followed by repeat local treatment is superior to upfront repeat local
treatment for the selected patient groups in terms of the primary objective
(OS). We hypothesize that neoadjuvant systemic therapy followed by repeat local
treatment is superior to upfront repeat local treatment for the selected
patient groups in terms of the primary objective (OS). The Cox proportional
hazards model (1-sided; superiority) and the PASKWIL criteria for adjuvant
treatment for the benefit of OS from the Dutch Society of Medical Oncology are
used for the sample size calculations. A total number of 360 patients will be
randomized (NR) into one of two arms: arm A (control group) upfront repeat
local treatment (n=180) and arm B (intervention group) 4 cycles of CAPOX
(capecitabine with oxaliplatin) +/- bevacizumab or 6 cycles of neoadjuvant
FOLFOX/FOLFIRI (5-fluorouracil/leucovorin with oxaliplatin or irinotecan) +/-
bevacizumab followed by repeat local treatment (n=180).

Eligible patients will be randomized into one of two arms: arm A (control
group) upfront repeat local treatment and arm B (intervention group) 12 weeks
of neoadjuvant systemic therapy followed by repeat local treatment. Patients in
arm B will receive maximum 4 cycles of CAPOX or 6 cycles of FOLFOX/FOLFIRI +/-
bevacizumab regardless of the location of primary tumor or RAS/BRAF mutation.
Choice of repeat local treatment is to the discretion of the local
investigator, and may be selected on a per patient basis.

Eligible patients will be stratified into two groups depending on the interval
between initial local treatment and first detection of recurrent CRLM:
recurrence within 6 months and recurrence between 6 and 12 months, RAS/BRAF
mutation vs RAS/BRAF wildtype, prognostic risk score (low vs high risk,
clinical risk score Fong et al. and previous chemotherapy versus no previous
chemotherapy.

When adhering to a maximum of 12 weeks of neoadjuvant systemic therapy, no
negative effect on procedural morbidity was found. Despite the possible damage
to the liver, there was no difference found in liver volume and function after
neoadjuvant systemic therapy before repeat local treatment. By participating in
the study, patients agree to either undergo neoadjuvant systemic therapy
followed by repeat local treatment for CRLM (intervention) or to undergo
upfront repeat local treatment (control). For each participant, the method of
treatment will be decided upon by randomization. Pre-operative work-up
screening will not be different from standard treatment and will not be an
additional burden. If participants receive systemic therapy before repeat local
treatment, we anticipate higher burden due to related systemic toxicity.
Follow-up after the procedure will be identical to standard treatment. If our
hypothesis will prove to be wrong, patients having undergone systemic therapy
before repeat local treatment are at risk of having a comparable overall
survival, comparable disease-free survival, and comparable local recurrence
rate, while the use of systemic therapy could lead to side-effects causing a
temporary or prolonged decrease in quality of life. If the addition of systemic
therapy to repeat local treatment proves to be superior to upfront repeat local
treatment, this patient group will have a prolonged life expectancy at the cost
of these side-effects.