Colon Cancer Liver MetastasesALPPSforCRLMNCT02758977
Associating Liver Partition With Portal Vein Ligation for Staged Hepatectomy (ALPPS) vs. Two-Stage Hepatectomy (TSH) for Marginally Resectable Colorectal Liver Metastases (CRLM)
A study testing ALPPS and TWO STAGE HEPATECTOMY in people with Colon Cancer Liver Metastases and Liver Neoplasms, run by University of Zurich at 1 site in Switzerland.
Trial summary
Surgical resection has offered the best option for prolonged survival in patients with colorectal liver metastases. Limiting factor for major liver resections is the size of the future liver remnant (FLR). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Colon Cancer Liver Metastases, Liver Neoplasms, Liver Diseases
- What is being tested?
- ALPPS and TWO STAGE HEPATECTOMY
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 214 participants
- Where
- 1 siteSwitzerland
- Study dates
- May 2016to Apr 2019
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients fulfilling all of the following inclusion criteria may be enrolled in the study:
- Male or female patients above 18 years of age.
- Patients with multifocal CRLM with a FLR/TLV (Total Liver Volume)< 30% OR a FLR/BW (Bodyweight) ratio of < 0.5.
- Patients with colorectal primary tumor not yet resected may be included as long as the extrahepatic disease may be cured surgically (liver first strategy).
- Patients with lung metastases may be included in the study as long as the lung metastases are potentially curable by resection by judgment of a thoracic surgery consultant.
- Chemotherapy response according to RECIST: regression or stable disease.
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- The indication for surgery should be discussed at a multidisciplinary tumor board attended by hepatobiliary surgeons, oncologists, hepatologists and radiologists.
- Written informed consent given by the patient after discussing the trial with the patient in a language he/she understands.
- For women of chlidbearing age: Not currently breastfeeding; usage of effective contraception if sexually active; not pregnant and agreement not to become pregnant during the 12 months thereafter. A negative pregnancy test before inclusion into the trial is required for women, who are not yet menopausal, had their last menses within less than 12 months or have not had uterus and or ovaries removed surgically or undergone tubal ligation.
Who cannot join
- The presence of any one of the following exclusion criteria will lead to exclusion of the participant:
- Male or female patients under 18 years of age.
- Unilobar tumorload qualifying the subject for a standard hepatectomy.
- Patients with multifocal CRLM with a FLR/TLV > 30% OR a FLR/BW ratio of > 0.5.
- Patients with a baseline FLR of less than 15%.
- Patients with extrahepatic metastatic disease (except potentially resectable lung metastases).
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- Patients not having received chemotherapy before study enrollment.
- If the liver biopsy prior to enrollment or the first liver biopsy in stage I shows fibrosis (Metavir stage ≥F3) or >30% macrosteatosis.
- Significant concomitant diseases making the patient unsuitable for major liver surgery by the judgment of the physicians involved.
- Known or suspected non-compliance (e.g. drug- and/or alcohol abuse).
- Enrollment into a clinical trial interfering with the endpoints.
- Intention to become pregnant during the course of the study.
- Lack of safe contraception, defined as: Female participants of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases.
- Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant.
- Previous enrollment in the current study.
Trial locations and contacts
1 site in 1 country.
Switzerland1 site
University Hospital
Zurich, Canton of Zurich, 8091
Marcel A Schneider, MD, 0041 442553300, MarcelAndre.Schneider@usz.ch
Pierre-Alain Clavien, MD PhD, 0041 442553300, clavien@access.uzh.ch
About this study
Official title: Associating Liver Partition With Portal Vein Ligation for Staged Hepatectomy (ALPPS) vs. Conventional Two-Stage Hepatectomy (TSH) for Surgical Treatment of Marginally Resectable Colorectal Liver Metastases (CRLM) - A Multicentric, Randomized Controlled Trial
Surgical resection has offered the best option for prolonged survival in patients with colorectal liver metastases. Limiting factor for major liver resections is the size of the future liver remnant (FLR). In case of normal liver function, 30% of the total liver volume is considered to be sufficient to maintain adequate liver function after resection. In an attempt to further increase "resectability" criteria for patients with too small FLR surgical and interventional maneuvers such as portal vein embolization and portal vein ligation in two-stage hepatectomies have been implemented, but they need an interval of 4-8 weeks to achieve sufficient hypertrophy. In order to obtain adequate but rapid parenchymal hypertrophy a new surgical two-step technique, ALPPS, was introduced for oncological patients requiring extended hepatic resection with limited functional reserve. Both procedures can be performed with acceptable morbidity and mortality.
The investigators conclude that it is time to perform a randomized study comparing the two surgical approaches in regard to oncological outcome.
- Conditions
- Colon Cancer Liver Metastases, Liver Neoplasms, Liver Diseases, Secondary Malignant Neoplasm of Liver, Malignant Neoplasm of Large Intestine Metastatic to Liver, Hepatectomy
- Being tested
- ALPPS, TWO STAGE HEPATECTOMY
- Keywords
- Colorectal liver metastases, Liver Surgery, ALPPS, Two Stage Hepatectomy, Surgical Oncology, Hepatectomy
- Medical subject headings
- Liver Neoplasms, Liver Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ALPPSProcedure or surgery
Also called Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy
For detailed information please refer to description of experimental arm
TWO STAGE HEPATECTOMYProcedure or surgery
Also called TSH
For detailed information please refer to description of active comparator arm
| Study group | Role | What they receive |
|---|---|---|
| ALPPS | Experimental | ASSOCIATING LIVER PARTITION WITH PORTAL VEIN LIGATION FOR STAGED HEPATECTOMY (ALPPS)
Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) is performed according to local practice in the respective centers. Preconditions to participation are experience with major liver resections and documentation of having performed at least 5 ALPPS cases prior to participation due to the learning curve with this quite complex procedure.
The amount of transsection (in-situ split/liver partition) in Step 1 is left to the participating center, no minimal % of transsection is specified. Receives: Procedure: ALPPS |
| TWO STAGE HEPATECTOMY | Active comparator | TWO STAGE HEPATECTOMY (TSH)
Two-Stage Hepatectomy is defined as:
1. Partial resection + portal vein ligation (RES PVL)
2. Partial resection + secondary portal vein embolization (RES PVE). Followed by (extended) hemihepatectomy after an interval to induce hypertrophy of the liver.
Conventional Two- Stage Hepatectomies will be standard procedures of the centers participating in the study. Receives: Procedure: TWO STAGE HEPATECTOMY |
What is being measured
The primary outcome is the main question the study is designed to answer.
1 Year Disease-free Survival
The primary objective will be disease-free survival at one year after randomization as determined by PET-CT (Positron emission tomography - Computer tomography), when not available by CT (Computer tomography) Thorax/Abdomen. This will be assessed by two independent radiologists who will be blinded to which arm the patient was enrolled in.
Patients who died, are lost to follow up or are too sick to undergo imaging will be censored and counted as failures to reach the primary endpoint.
Patients may need resection of their primary tumor after the study intervention (liver first strategy). They may develop recurrence within the study period, systemic or in the liver. In these patients ablation, reoperation and chemotherapy are used as customary clinical routine. Whether they achieved tumor free survival however depends only on the PET-CT or CT Thorax Abdomen at one year.
Measured: 1 year after Randomization
Secondary outcomes (10)
Procedure-associated Mortality
All deaths will be recorded in the 12 month-period after randomization. Specifically, the number of patients, which suffer a fatal event due to the procedure during the postoperative period, will be calculated to assess the safety of the two interventions.
Measured: Up to 1 year after Randomization
Procedure-associated Complications
Complications during the postoperative period will be recorded using the Clavien-Dindo Classification, also known as the Zurich Classification, which grades surgical Complications on a scale from 1 to 5 (death of patient).
Dindo D, Demartines N, Clavien PA: Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 Aug;240(2):205-13.
Measured: Up to 1 year after Randomization
Percentage of patients in which complete curative two-staged surgery was possible.
The percentage of patients, in which a complete curative two-staged surgical procedure was possible, will be assessed.
"Complete" is defined as successful completion of both surgical steps of the procedure, i.e.:
- step 1: cleaning of tumorlesions in the future liver remnant (FLR) and portal vein ligation of the contralateral segments to induce hypertrophy of the FLR (with or without in situ split/transsection).
- step 2: resection of the tumorbearing part of the liver, leaving a tumor-free FLR in situ.
"Curative" is defined as achieving a tumorfree FLR after step 2 with no signs of extrahepatic tumor existance.
(If patients have the primary tumor or potentially resectable lung metastases, which will be approached surgically in the future treatment of the patient in a curative intent, then the procedure does count as curative).
Measured: Up to 1 year after Randomization
Complete (R0) vs. incomplete (R1/2) resection (oncological outcome)
A consensus between pathologists and surgeons on the R-status of the resection, judging both stages separately and together. Through re-resection R0 may be achieved overall even if there was a R1 resection after stage 1.
Measured: 1 year after Randomization
Overall survival (oncological outcome)
From date of randomization until the date of death from any cause, assessed up to 10 years.
Regular further follow up-visits after assessment of the primary endpoint at 1 year are planned 1.5, 2, 3, 5 and 10 years after Randomization.
Measured: Up to 10 years after Randomization
Quality of Life (QoL)
Will be evaluated by the Visual Analogue Scale (VAS) for Quality of Life in Cancer.
Visual Analogue Scale determines QoL on a scale of 1 (worst) to 10 (best).
First Baseline Assessment before stage 1 procedure. Assessment after procedure step 1. Assessment before stage 2 procedure. Assessment after procedure step 2. Regular assessments during scheduled and unscheduled follow-up visits.
Measured: Up to 1 year after Randomization
Radiographic liver volumetric changes
Volumetry 1 performed before stage 1 of procedure Volumetry 2 performed before stage 2 of procedure
All volumetries are performed locally via magnet resonance Imaging or computertomography and reported into a respective volumetry Case Report Form (CRF).
Measured: Up to 1 year after Randomization
Incidence of posthepatectomy liver failure
The incidence of posthepatectomy liver failure is assessed according to the definition and grading by the International Study Group of Liver Surgery (ISGLS), which separates 3 different grades of posthepatectomy liver failure (Grade A to C).
Rahbari, N. N., et al. (2011). "Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS)." Surgery 149(5): 713-724.
Measured: Up to 1 year after Randomization
Incidence of posthepatectomy liver failure
The incidence of posthepatectomy liver failure is assessed according too the "50:50 Criteria".
Balzan, S., et al. (2005). "The "50-50 criteria" on postoperative day 5: an accurate predictor of liver failure and death after hepatectomy." Ann Surg 242(6): 824-828, discussion 828-829.
Measured: Up to 1 year after Randomization
Incidence of posthepatectomy renal failure
Measurement of the following parameter at screening visit, during the postoperative course of stage 1 \& 2 (postoperative days 1,2,3,5,7) and at follow-up visits:
- Creatinin [Unit: µmol/l]
This parameter is used to calculate and assess the incidence of posthepatecomy renal failure according to the AKIN-criteria.
Ricci, Z., et al. (2011). "Classification and staging of acute kidney injury: beyond the RIFLE and AKIN criteria." Nat Rev Nephrol 7(4): 201-208.
Measured: Up to 1 year after Randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 May 2016 (estimated)
- Study startMay 2016
- Primary completionApr 2019 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Colon Cancer Liver MetastasesStudies of the same condition, open and under way.
- More trials run by University of ZurichThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 214 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Zurich
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Pierre-Alain Clavien, MD, PhD, Principal investigator, University of Zurich
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02758977
- Sponsor's protocol ID
- 2015-0024
- Acronym
- ALPPSforCRLM
- Status last verified
- Apr 2016
- First submitted
- 5 Apr 2016
- Last updated
- 3 May 2016
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 May 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Associating Liver Partition With Portal Vein Ligation for Staged Hepatectomy (ALPPS) vs. Conventional Two-Stage Hepatectomy (TSH) for Surgical Treatment of Marginally Resectable Colorectal Liver Metastases (CRLM) - A Multicentric, Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT02758977
- Acronym / sponsor ID
- ALPPSforCRLM / 2015-0024
- Conditions
- Colon Cancer Liver Metastases, Liver Neoplasms, Liver Diseases, Secondary Malignant Neoplasm of Liver, Malignant Neoplasm of Large Intestine Metastatic to Liver, Hepatectomy
- Keywords
- Colorectal liver metastases, Liver Surgery, ALPPS, Two Stage Hepatectomy, Surgical Oncology, Hepatectomy
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 214 participants (estimated)
- Lead sponsor
- University of ZurichUniversity, hospital or other
- Study start
- May 2016
- Primary completion
- Apr 2019 (estimated)
- First posted
- 3 May 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Surgical resection has offered the best option for prolonged survival in patients with colorectal liver metastases. Limiting factor for major liver resections is the size of the future liver remnant (FLR). In case of normal liver function, 30% of the total liver volume is considered to be sufficient to maintain adequate liver function after resection. In an attempt to further increase "resectability" criteria for patients with too small FLR surgical and interventional maneuvers such as portal vein embolization and portal vein ligation in two-stage hepatectomies have been implemented, but they need an interval of 4-8 weeks to achieve sufficient hypertrophy. In order to obtain adequate but rapid parenchymal hypertrophy a new surgical two-step technique, ALPPS, was introduced for oncological patients requiring extended hepatic resection with limited functional reserve. Both procedures can be performed with acceptable morbidity and mortality.
The investigators conclude that it is time to perform a randomized study comparing the two surgical approaches in regard to oncological outcome.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| ALPPS | Experimental | Procedure: ALPPSASSOCIATING LIVER PARTITION WITH PORTAL VEIN LIGATION FOR STAGED HEPATECTOMY (ALPPS) Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) is performed according to local practice in the respective centers. Preconditions to participation are experience with major liver resections and documentation of having performed at least 5 ALPPS cases prior to participation due to the learning curve with this quite complex procedure. The amount of transsection (in-situ split/liver partition) in Step 1 is left to the participating center, no minimal % of transsection is specified. |
| TWO STAGE HEPATECTOMY | Active comparator | Procedure: TWO STAGE HEPATECTOMYTWO STAGE HEPATECTOMY (TSH) Two-Stage Hepatectomy is defined as: 1. Partial resection + portal vein ligation (RES PVL) 2. Partial resection + secondary portal vein embolization (RES PVE). Followed by (extended) hemihepatectomy after an interval to induce hypertrophy of the liver. Conventional Two- Stage Hepatectomies will be standard procedures of the centers participating in the study. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Male or female patients above 18 years of age.
- Patients with multifocal CRLM with a FLR/TLV (Total Liver Volume)< 30% OR a FLR/BW (Bodyweight) ratio of < 0.5.
- Patients with colorectal primary tumor not yet resected may be included as long as the extrahepatic disease may be cured surgically (liver first strategy).
- Patients with lung metastases may be included in the study as long as the lung metastases are potentially curable by resection by judgment of a thoracic surgery consultant.
- Chemotherapy response according to RECIST: regression or stable disease.
Key exclusion criteria (15 listed)
- The presence of any one of the following exclusion criteria will lead to exclusion of the participant:
- Male or female patients under 18 years of age.
- Unilobar tumorload qualifying the subject for a standard hepatectomy.
- Patients with multifocal CRLM with a FLR/TLV > 30% OR a FLR/BW ratio of > 0.5.
- Patients with a baseline FLR of less than 15%.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ALPPSAlso: Associating Liver Partition and Portal Vein Ligation for Staged HepatectomyFor detailed information please refer to description of experimental arm | Procedure or surgery | ALPPS |
| TWO STAGE HEPATECTOMYAlso: TSHFor detailed information please refer to description of active comparator arm | Procedure or surgery | TWO STAGE HEPATECTOMY |
Primary outcome
1 Year Disease-free Survival
Time frame: 1 year after Randomization
The primary objective will be disease-free survival at one year after randomization as determined by PET-CT (Positron emission tomography - Computer tomography), when not available by CT (Computer tomography) Thorax/Abdomen. This will be assessed by two independent radiologists who will be blinded to which arm the patient was enrolled in. Patients who died, are lost to follow up or are too sick to undergo imaging will be censored and counted as failures to reach the primary endpoint. Patients may need resection of their primary tumor after the study intervention (liver first strategy). They may develop recurrence within the study period, systemic or in the liver. In these patients ablation, reoperation and chemotherapy are used as customary clinical routine. Whether they achieved tumor free survival however depends only on the PET-CT or CT Thorax Abdomen at one year.
10 secondary outcomes
Procedure-associated Mortality
Time frame: Up to 1 year after Randomization
Procedure-associated Complications
Time frame: Up to 1 year after Randomization
Percentage of patients in which complete curative two-staged surgery was possible.
Time frame: Up to 1 year after Randomization
Complete (R0) vs. incomplete (R1/2) resection (oncological outcome)
Time frame: 1 year after Randomization
Overall survival (oncological outcome)
Time frame: Up to 10 years after Randomization
Quality of Life (QoL)
Time frame: Up to 1 year after Randomization
Radiographic liver volumetric changes
Time frame: Up to 1 year after Randomization
Incidence of posthepatectomy liver failure
Time frame: Up to 1 year after Randomization
Incidence of posthepatectomy liver failure
Time frame: Up to 1 year after Randomization
Incidence of posthepatectomy renal failure
Time frame: Up to 1 year after Randomization
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 May 2016.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Pierre-Alain Clavien, MD, PhD principal investigator
University of Zurich
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing ALPPS and TWO STAGE HEPATECTOMY in people with Colon Cancer Liver Metastases and Liver Neoplasms, run by University of Zurich at 1 site in Switzerland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 3 May 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Marcel A Schneider, MD (0041 442553300, MarcelAndre.Schneider@usz.ch), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
1 Year Disease-free Survival (time frame: 1 year after Randomization). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 May 2016.