Microwave Ablation Versus Resection for Resectable Colorectal Liver Metastases
Condition: Neoplasm Metastasis
MeSH terms: Neoplasm Metastasis
Study type: Observational [Patient Registry]

Summary: 
      This study aims to prove that a strategy of first line local ablation of colorectal liver
      metastases with microwaves is not inferior to liver resections in terms of survival rates at
      three years with secondary endpoints being survival at five and ten years, interventional
      complication rates, length of stay, ablation precision measurements, need for further
      interventions and health-economic analysis.

      A cohort of 100 patients treated with CT guided microwave ablation of 1-5 metastases <31mm in
      size will be followed and compared with propensity scored matched controls from the Swedish
      liver surgery registry - Sweliv.

      The study is a multi-institutional effort by the Hepato Pancreatico Biliary (HPB) units in
      Stockholm Sweden, Bern Switzerland and Groningen in the Netherlands.
    

Detailed description: 
      BACKGROUND

      Surgery Surgical resection of operable colorectal liver metastases is the current gold
      standard. With advancement in surgical techniques and technology the 3-year survival rate for
      this group of patients is now in the range of 60% [1] where the survival without resection is
      virtually non-existent. Palliative chemotherapy can prolong survival for 12-24 months, but
      very rarely much more than this [2].

      Operability is decided by the general health condition of the patient, the global liver
      function and tumour associated factors like the number, size and distribution of the liver
      metastases.

      It is uncommon to disqualify surgery because of the general health of the patient, but is
      sometimes a reality with advanced age and severe comorbidities.

      The combination of size, number and distribution of liver metastases determines the extent of
      the resection and thereby the size of the liver that will remain after surgery. This is a
      critical factor as postoperative liver failure is often fatal. With an otherwise healthy
      liver, approximately 75% of the parenchyma can be resected and the remaining 25% will within
      a year has regenerated so that the total liver volume is around 80-90% of the original liver
      [3].

      This regenerative capacity is used to make complex resections in stages, there by
      manipulating an initially small liver remnant to a sufficient size for survival.

      Liver surgery, however, comes with a price. For small local resections and laparoscopic minor
      hepatectomies the morbidity of surgery is 20-30% with a quarter being serious. For major and
      complex procedures the morbidity is 40-50% with the same proportion of serious complications
      requiring further surgical intervention or death [4]. With advanced patient support and state
      of the art surgical technique, the mortality following surgery is small, typically in the
      range of 1-2%.

      The patients spend 5-14 days in hospital and are incapacitated for a month or two after open
      surgery, significantly less after laparoscopic surgery where the patient usually can return
      home after 2-7 days in hospital and with an early return to normal physical activities within
      two weeks.

      Another factor to take into account is the frequency of liver recurrences. After resection,
      50-80% of the patients will get new liver metastases [5]. With previous major resections the
      choice of following surgical strategies gets more limited.

      Ablations Local ablation techniques have evolved from local injection of cytotoxic agents
      like ethanol and acetic acid to thermal ablations with freezing of the tissue or heating with
      radiofrequency energy, laser beams or microwave energy. Ablations can also be done by
      destroying cell membranes with electricity in short intense bursts, the irreversible
      electroporation technique, causing localised cell death with very little heat thereby
      preserving collagen structures and other surrounding proteins, which will result in patent
      vessels, bile-ducts and nerve sheaths [6].

      The ablative procedures have two critical points; the correct localization of the energy and
      the correct amount of energy. Ablation in the wrong place will decrease the efficacy as will
      an incorrect size of the ablation.

      Targeting of lesions has improved with computer assisted targeting and fusion of radiological
      modalities so that as much information as possible can be used in the placement of the energy
      source. Percutaneous ultrasound targeting has until recently been the most common means of
      placing ablation devices in liver lesions. Local recurrence rates of 20-30% are typically
      reported with this approach. With more recent fused and computer assisted techniques the
      local recurrence rate is often stated to be around 5-10% [7].

      The main limitation with ablative techniques is the size of the lesions. Many studies have
      shown a good result with lesion less than 30mm in diameter and increasing recurrence rates
      with larger lesions. A single ablation can usually only be up to 40-50mm in diameter. Larger
      lesions can be treated with multiple applications but the geometries of ovoid ablations in
      irregular tumours makes complete ablations difficult.

      Destroying lesions with ablative techniques spares liver parenchyma and allows for treating
      patients that are not resectable in situations with multiple lesions engaging all or most of
      the liver segments. This approach has greatly increased the survival in this group of
      patients. Sparing unaffected liver parenchyma also increases the flexibility when there are
      liver recurrences of metastatic disease. This happens in up to 50 percent of patients after
      local resections and ablations and in a third of patients after major hepatectomies and with
      a focused ablative approach more functioning liver parenchyma can be saved and the options
      for treatment of recurrences are wider.

      Lesions can be targeted with a percutaneous approach using ultrasound fused with magnetic
      resonance imaging or computer tomography, or in the CT with guidance techniques, or
      laparoscopically if needed. Very rarely an open approach is needed.

      This means that patients usually goes home the same day or the day after treatment and has
      returned to normal physical activities within a week.

      Morbidity is in the area of 10% with a fourth being serious complications requiring some kind
      of intervention. Mortality is typically very low and under 1%.

      Local thermal ablations have been shown to be equal to resections in the treatment in
      hepatocellular carcinoma when lesions are less than 30mm in size. These data come from
      retrospective analyses of single centre experiences and are as such of low scientific grade
      of evidence [8,9].

      Study design considerations There has not been any well-powered randomized study comparing an
      ablative strategy with a resective. Doing a non-inferiority randomized study with sufficient
      power would need up to a thousand patients in each group, thus making this study virtually
      impossible to conduct. A way to come around this is to use propensity score techniques to
      compare cases with controls. The investigators have well documented controls in the swedish
      liver registry allowing for propensity score matching of the data.

      With this design only 100 patients will have to be treated, as has been computed with a power
      calculation with survival curves after resective treatment with colorectal liver metastases.
      Data was extracted from "Livermet survey", an on-line prospective database with more than
      25000 hepatectomies for colorectal cancer in 69 countries. Data for a first resection of a
      single metastasis smaller than 30mm (best case scenario) was extracted and survival curves
      computed. With a non-inferiority assumption, with a power of 90% and the non-inferiority
      limit being not worse than 5% reduction in 3-year survival, a sample size of 100 was
      computed, see figure below.

      CLINICAL AND ECONOMICAL CONSEQUENCES If the study thesis holds there would be a great impact
      on the treatment of colorectal liver metastases where approximately half could be treated
      with a minimal invasive and low-complication ablation strategy, greatly reducing patient
      morbidity and increasing possibilities for further treatment modalities in case of tumour
      recurrences in the liver. With much shorter hospital stay and sick-leave there is a great
      potential for big savings in health-related costs for health service providers.

      From Engstrand et al. In manuscript. This shows the distribution of 272 liver metastases from
      colorectal cancer among a population based cohort of 1032 patients that were diagnosed with
      that primary in the greater Stockholm area in 2008. Approximately half of all patients
      eligible for resection could potentially be treated with ablation.

      STUDY DESIGN European multicentre prospective cohort study with propensity score matching for
      number or tumours, age, gender and response to chemotherapy (no chemo - response/stable
      disease - progression).

      Patients with colorectal liver metastases are evaluated at a weekly liver multidisciplinary
      conference and a treatment strategy is decided. In this decision process patients that are
      resectable and have tumours of 30mm or less and not more than 5 in number, and deemed as both
      ablatable and resectable, will be offered treatment with an ablative strategy using state of
      the art targeting and microwave ablation devices. During the study inclusion phase, which can
      be sequential or with specific weeks during the year (one in two/three/four/five depending on
      local considerations), all patients that fulfill the inclusion criteria must be entered into
      the database. All ablations will be done with computer assisted CT targeting (Cascination AG,
      Bern, Ch) allowing for precise image documentation and evaluation of tumour, ablation device
      placement and resulting ablation zones. Repeat ablation is allowed and a new
      multidisciplinary team conference (MDT) discussion is mandated with loss of disease control.

      Patient characteristics and procedure related parameters will be recorded and outcome
      measured as overall survival at three years using survival analysis. Secondary outcomes will
      be tumour state (disease free interval), complications, local recurrence rates, accuracy in
      placement of ablative device, analyses of ablation volumes, length of stay and further need
      of treatment with ablations or resections.

      Treatment with chemotherapy will be as decided at the MDT and with the same protocol that is
      used with neoadjuvant or adjuvant treatment with surgical resection.

      Patients will give their informed consent before entering the study.

      Patient data will be stored in a secure password-protected server with Red-cap software
      belonging to Karolinska Institutet at Danderyd Hospital. Procedural data will be stored
      together with image series downloaded directly from the ablation aiming device to Artorg
      Centre at the University of Bern, responsible for volumetric and precisional data analyses in
      the study.

      Patient recruitment will primarily be from the greater Stockholm area. All treatment of
      swedish patients will be at Danderyd Hospital, Stockholm Sweden.

      A second centre will be at Inselspital in Bern, Switzerland, and a third in Groningen in the
      Netherlands.

      With an optimal inclusion rate the study will have recruited the necessary patients within
      one year.

      TIME FRAME September 1: finalization of protocol and submission to ethics board November
      2015: Start inclusion November 2017?: Inclusion complete 2018: Publication of intervention
      specific data like workflow, precision and ablation volumes.

      2020: Three year follow-up finished and files closed for main study 2021: Publication of
      results 2023: Evaluation and publication of 5-year survival data 2028: Evaluation and
      publication of 10-year survival data. Database finally closed.
    

Intervention name(s): Microwave ablation; Resection
Intervention type(s): Procedure; Procedure
Intervention description(s): CT-guided percutaneous ablation of 1-5, <31mm in diameter, colorectal liver metastases, performed with any generic microwave ablation system cleared for clinical use; Open or laparoscopic resection of liver metastases using standard of care surgical procedures
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        European multicentre prospective cohort study with propensity score matching for number or
        tumours, age, gender and response to chemotherapy (no chemo - response/stable disease -
        progression).

        Patients with colorectal liver metastases are evaluated at a weekly liver multidisciplinary
        conference and a treatment strategy is decided. In this decision process patients that are
        resectable and have tumours of 30mm or less and not more than 5 in number, and deemed as
        both ablatable and resectable, will be offered treatment with an ablative strategy using
        state of the art targeting and microwave ablation devices.
      
Keywords: microwave; ablation; resection; liver; colorectal; survival; metastasis