LDLT in Non Resectable Colo-rectal Cancer Liver Metastasis

Liver Metastasis Colon Cancer Clinical Trial

— LIVERMORE  

Official title:

Living Donor Liver Transplantation (LDLT) in Non Resectable Colo-rectal Cancer Liver Metastasis. The LIVERMORE Trial (LIVing Donor livEr tRansplant Modena cOloRectal mEtastasis) [Original Title in Italian: "Trapianto di Fegato da Donatore Vivente Per Metastasi Epatiche Non Resecabili da Adenocarcinoma Del Colon"]

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05186116
• Other study ID #: 470/2021/SPER/AOUMO
• Status: Recruiting
• Phase: N/A
• Start date: January 1, 2022
• Est. completion date: January 1, 2032

Study information

• Verified date: April 2024
• Source: Azienda Ospedaliero-Universitaria di Modena
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is an interventional open label prospective study that aims to assess both overall and disease-free survival of patients treated with LDLT, partial or whole graft LT from deceased donors for unresectable CRLM.

Secondary outcomes are graft survival and donor outcomes in terms of safety and quality of life.

Donor selection is performed according to the currently used Institutional and National standards and protocols.

Description:

Liver Transplant (LT) is a feasible, safe and effective curative strategy for patients with unresectable colorectal liver metastases (CRLM), and several trials are currently active and in a recruitment phase to study its impact with both conventional donors and living donors (LDLT).

As a matter of fact, in this setting living donors represent a helpful resource, thanks to the opportunity to schedule the LT at the timeliest conditions in terms of oncological response and patient's performance status. LDLT is a well-established procedure that is already offered to patients listed for LT at our Institution.

Crucial requirement for study eligibility is the assessment of non-resectability of the presented liver metastases from colorectal cancer (CRC).

Criteria for non-resectability of the liver-only CRC metastases eligible for the study should be assessed at the patient study entry, by the surgeon in charge together with the multidisciplinary team.

Patients fulfilling the inclusion criteria of the study will undergo clinical, translational and regulatory steps. Briefly, the main procedures and requirements of the study can be summarized as follows:

• Pre-transplant screening and waiting phase:

Screening of patients with liver-limited CRC metastases potentially eligible to the study will be registered. The screening for general eligibility to liver transplantation will be conducted according to the existing Institutional protocol (called in Italian "PDTA", "Percorso Diagnostico Terapeutico Assistenziale").

During screening or waiting time periods, patients will continue planned chemotherapy treatment and will undergo blood tests (including CEA and Ca19.9), thoraco-abdominal CT scan and positron emission tomography (PET) scan (if needed) every 8 weeks.

• Donors' screening:

Screening of donors will be held according to the existing Institutional protocol for LDLT

• Informed consent:

Consent to the study will be signed after completion of the pre-LT screening, that is once co-morbidities and transplant eligibility will be ascertained on top of cancer conditions. In addition, patients will have to sign additional written informed consent prior to any study procedure.

• Post-transplant follow-up:

Following LDLT, standard institutional follow-up procedures will be performed and registered. Patient/graft condition and tumor status should be re-assessed at least every 4 months for the first 3 years, every 6 months for the rest of follow-up.

Following donation standard institutional follow up will be performed on donors and registered.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 25
• Est. completion date: January 1, 2032
• Est. primary completion date: January 1, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 77 Years

Eligibility

Inclusion Criteria:

• Age =18.

• Histologically confirmed colon and rectum (intraperitoneal) adenocarcinoma.

• Pathological classification of primary tumor as pT1-3, pN0 or pN1 (metastases in < 4 regional lymph nodes), without peritoneal tumor deposits, absence of mucinous component >50%, confirmed R0 resection, no limitations for RAS mutations, B-RAF wild type.

• No signs of extra hepatic metastatic disease or local recurrence according to CT scan+MRI+PET/CT scans.

• Liver metastases not eligible for curative liver resection

• Objective response according to RECIST 1.1 to first-line treatment, with sustained response for at least 4 months, OR disease control (complete [CR] or partial response [PR] or standard disease [SD]) during second- line treatment for at least 4 months.

• Carcinoembryonic Antigen (CEA) values stable or decreasing during the enrollment prior to liver transplant.

• Performance status, ECOG (Eastern Cooperative Oncology Group) 0-2.

• Signed informed consent and expected cooperation of the patients for the treatment and follow-up, and national/local regulations.

Exclusion Criteria:

• Hereditary CRC syndromes including FAP (Familial adenomatous polyposis) and Lynch syndrome.

• Prior extra hepatic metastatic disease or primary tumor local relapse.

• Palliative resection of primary CRC tumor.

• Disease progression

• Other malignancies in the previous 5 years (with exception of in situ cervical carcinoma and basal cell carcinoma; superficial bladder tumors are allowed if curatively treated).

• Active intra-venous or alcohol abusers (patients may be eligible if abstention > 6 months is demonstrated)

• Active HIV infection

• Psychiatric disorders and patient low compliance

• Any reason why, in the judgment of the investigators, the patient should not participate (to be formally declared)

Related Conditions & MeSH terms

• Adenocarcinoma
• Colon Adenocarcinoma
• Colonic Neoplasms
• Liver Metastasis Colon Cancer
• Liver Neoplasms
• Neoplasm Metastasis

Intervention

Procedure:
• Living donor liver transplant, Split liver transplant, RAPID, DDLT
Transplantation of part of the liver from a living donor, or entire cadaveric graft

Locations

Country	Name	City	State
Italy	Azienda Ospedaliero Universitaria di Modena	Modena	MO

Sponsors (1)

Lead Sponsor	Collaborator
Azienda Ospedaliero-Universitaria di Modena

Country where clinical trial is conducted

Italy, 

References & Publications (33)

Abdalla EK, Hicks ME, Vauthey JN. Portal vein embolization: rationale, technique and future prospects. Br J Surg. 2001 Feb;88(2):165-75. doi: 10.1046/j.1365-2168.2001.01658.x. — View Citation

Bonney GK, Chew CA, Lodge P, Hubbard J, Halazun KJ, Trunecka P, Muiesan P, Mirza DF, Isaac J, Laing RW, Iyer SG, Chee CE, Yong WP, Muthiah MD, Panaro F, Sanabria J, Grothey A, Moodley K, Chau I, Chan ACY, Wang CC, Menon K, Sapisochin G, Hagness M, Dueland — View Citation

Brudvik KW, Vauthey JN. Surgery: KRAS mutations and hepatic recurrence after treatment of colorectal liver metastases. Nat Rev Gastroenterol Hepatol. 2017 Nov;14(11):638-639. doi: 10.1038/nrgastro.2017.129. Epub 2017 Sep 20. No abstract available. — View Citation

Butte JM, Gonen M, Allen PJ, Peter Kingham T, Sofocleous CT, DeMatteo RP, Fong Y, Kemeny NE, Jarnagin WR, D'Angelica MI. Recurrence After Partial Hepatectomy for Metastatic Colorectal Cancer: Potentially Curative Role of Salvage Repeat Resection. Ann Surg — View Citation

Cremolini C, Casagrande M, Loupakis F, Aprile G, Bergamo F, Masi G, Moretto R R, Pietrantonio F, Marmorino F, Zucchelli G, Tomasello G, Tonini G, Allegrini G, Granetto C, Ferrari L, Urbani L, Cillo U, Pilati P, Sensi E, Pellegrinelli A, Milione M, Fontani — View Citation

D'Angelica M, Kornprat P, Gonen M, DeMatteo RP, Fong Y, Blumgart LH, Jarnagin WR. Effect on outcome of recurrence patterns after hepatectomy for colorectal metastases. Ann Surg Oncol. 2011 Apr;18(4):1096-103. doi: 10.1245/s10434-010-1409-1. Epub 2010 Nov — View Citation

Dueland S, Foss A, Solheim JM, Hagness M, Line PD. Survival following liver transplantation for liver-only colorectal metastases compared with hepatocellular carcinoma. Br J Surg. 2018 May;105(6):736-742. doi: 10.1002/bjs.10769. Epub 2018 Mar 13. — View Citation

Dueland S, Grut H, Syversveen T, Hagness M, Line PD. Selection criteria related to long-term survival following liver transplantation for colorectal liver metastasis. Am J Transplant. 2020 Feb;20(2):530-537. doi: 10.1111/ajt.15682. Epub 2019 Nov 28. — View Citation

Dueland S, Syversveen T, Solheim JM, Solberg S, Grut H, Bjornbeth BA, Hagness M, Line PD. Survival Following Liver Transplantation for Patients With Nonresectable Liver-only Colorectal Metastases. Ann Surg. 2020 Feb;271(2):212-218. doi: 10.1097/SLA.000000 — View Citation

Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999 Sep;230(3):309-18; discussion 318-21. doi: 10.1097/00 — View Citation

Grat M, Krawczyk M, Stypulkowski J, Morawski M, Krasnodebski M, Wasilewicz M, Lewandowski Z, Grat K, Patkowski W, Zieniewicz K. Prognostic Relevance of a Complete Pathologic Response in Liver Transplantation for Hepatocellular Carcinoma. Ann Surg Oncol. 2 — View Citation

Grut H, Dueland S, Line PD, Revheim ME. The prognostic value of 18F-FDG PET/CT prior to liver transplantation for nonresectable colorectal liver metastases. Eur J Nucl Med Mol Imaging. 2018 Feb;45(2):218-225. doi: 10.1007/s00259-017-3843-9. Epub 2017 Oct — View Citation

Grut H, Solberg S, Seierstad T, Revheim ME, Egge TS, Larsen SG, Line PD, Dueland S. Growth rates of pulmonary metastases after liver transplantation for unresectable colorectal liver metastases. Br J Surg. 2018 Feb;105(3):295-301. doi: 10.1002/bjs.10651. — View Citation

Hagness M, Foss A, Egge TS, Dueland S. Patterns of recurrence after liver transplantation for nonresectable liver metastases from colorectal cancer. Ann Surg Oncol. 2014 Apr;21(4):1323-9. doi: 10.1245/s10434-013-3449-9. Epub 2013 Dec 27. — View Citation

Hill CR, Chagpar RB, Callender GG, Brown RE, Gilbert JE, Martin RC 2nd, McMasters KM, Scoggins CR. recurrence following hepatectomy for metastatic colorectal cancer: development of a model that predicts patterns of recurrence and survival. Ann Surg Oncol. — View Citation

Kanas GP, Taylor A, Primrose JN, Langeberg WJ, Kelsh MA, Mowat FS, Alexander DD, Choti MA, Poston G. Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors. Clin Epidemiol. 2012;4:283-301. doi: 10.21 — View Citation

Konigsrainer A, Templin S, Capobianco I, Konigsrainer I, Bitzer M, Zender L, Sipos B, Kanz L, Wagner S, Nadalin S. Paradigm Shift in the Management of Irresectable Colorectal Liver Metastases: Living Donor Auxiliary Partial Orthotopic Liver Transplantatio — View Citation

Ladner DP, Dew MA, Forney S, Gillespie BW, Brown RS Jr, Merion RM, Freise CE, Hayashi PH, Hong JC, Ashworth A, Berg CL, Burton JR Jr, Shaked A, Butt Z. Long-term quality of life after liver donation in the adult to adult living donor liver transplantation — View Citation

Lang H, de Santibanes E, Schlitt HJ, Malago M, van Gulik T, Machado MA, Jovine E, Heinrich S, Ettorre GM, Chan A, Hernandez-Alejandro R, Robles Campos R, Sandstrom P, Linecker M, Clavien PA. 10th Anniversary of ALPPS-Lessons Learned and quo Vadis. Ann Sur — View Citation

Line PD, Hagness M, Berstad AE, Foss A, Dueland S. A Novel Concept for Partial Liver Transplantation in Nonresectable Colorectal Liver Metastases: The RAPID Concept. Ann Surg. 2015 Jul;262(1):e5-9. doi: 10.1097/SLA.0000000000001165. — View Citation

Line PD, Ruffolo LI, Toso C, Dueland S, Nadalin S, Hernandez-Alejandro R. Liver transplantation for colorectal liver metastases: What do we need to know? Int J Surg. 2020 Oct;82S:87-92. doi: 10.1016/j.ijsu.2020.03.079. Epub 2020 Apr 17. — View Citation

Marcus L, Lemery SJ, Keegan P, Pazdur R. FDA Approval Summary: Pembrolizumab for the Treatment of Microsatellite Instability-High Solid Tumors. Clin Cancer Res. 2019 Jul 1;25(13):3753-3758. doi: 10.1158/1078-0432.CCR-18-4070. Epub 2019 Feb 20. — View Citation

Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996 Mar 14;334(11): — View Citation

Missiaglia E, Jacobs B, D'Ario G, Di Narzo AF, Soneson C, Budinska E, Popovici V, Vecchione L, Gerster S, Yan P, Roth AD, Klingbiel D, Bosman FT, Delorenzi M, Tejpar S. Distal and proximal colon cancers differ in terms of molecular, pathological, and clin — View Citation

Moris D, Tsilimigras DI, Chakedis J, Beal EW, Felekouras E, Vernadakis S, Schizas D, Fung JJ, Pawlik TM. Liver transplantation for unresectable colorectal liver metastases: A systematic review. J Surg Oncol. 2017 Sep;116(3):288-297. doi: 10.1002/jso.24671 — View Citation

Muhlbacher F, Huk I, Steininger R, Gnant M, Gotzinger P, Wamser P, Banhegyi C, Piza F. Is orthotopic liver transplantation a feasible treatment for secondary cancer of the liver? Transplant Proc. 1991 Feb;23(1 Pt 2):1567-8. No abstract available. — View Citation

Pawlik TM, Schulick RD, Choti MA. Expanding criteria for resectability of colorectal liver metastases. Oncologist. 2008 Jan;13(1):51-64. doi: 10.1634/theoncologist.2007-0142. — View Citation

Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014 Jun 1;74(11):2913-21. doi: 10.11 — View Citation

Sartore-Bianchi A, Trusolino L, Martino C, Bencardino K, Lonardi S, Bergamo F, Zagonel V, Leone F, Depetris I, Martinelli E, Troiani T, Ciardiello F, Racca P, Bertotti A, Siravegna G, Torri V, Amatu A, Ghezzi S, Marrapese G, Palmeri L, Valtorta E, Cassing — View Citation

Sinha PK, Mohapatra N, Bharathy KG, Kumar G, Pamecha V. A Long-Term Prospective Study of Quality of Life, Abdominal Symptoms, and Cosmesis of Donors After Hepatectomy for Live-Donor Liver Transplantation. J Clin Exp Hepatol. 2021 Sep-Oct;11(5):579-585. do — View Citation

Toso C, Pinto Marques H, Andres A, Castro Sousa F, Adam R, Kalil A, Clavien PA, Furtado E, Barroso E, Bismuth H; Compagnons Hepato-Biliaires Group. Liver transplantation for colorectal liver metastasis: Survival without recurrence can be achieved. Liver T — View Citation

Tsai MS, Su YH, Ho MC, Liang JT, Chen TP, Lai HS, Lee PH. Clinicopathological features and prognosis in resectable synchronous and metachronous colorectal liver metastasis. Ann Surg Oncol. 2007 Feb;14(2):786-94. doi: 10.1245/s10434-006-9215-5. Epub 2006 N — View Citation

Wicherts DA, de Haas RJ, Salloum C, Andreani P, Pascal G, Sotirov D, Adam R, Castaing D, Azoulay D. Repeat hepatectomy for recurrent colorectal metastases. Br J Surg. 2013 May;100(6):808-18. doi: 10.1002/bjs.9088. Epub 2013 Mar 12. — View Citation

* Note: There are 33 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival	Overall survival of patients treated with LDLT for unresectable CRLM compared to our historical cohort of potentially transplantable patients that underwent chemotherapy only	5 years
Primary	Disease free survival	Disease-free survival of patients treated with LDLT for unresectable CRLM compared to our historical cohort of potentially transplantable patients that underwent chemotherapy only	5 years
Secondary	Graft survival	Incidence of retransplant in the LDLT group	5 years
Secondary	Donor quality of life	Measure of Health-related quality of life (HRQOL) of donors using the a Short Form Health Survey 36 (SF-36). SF-36 is a multiplanar scale with scores ranging from 0 to 100 where zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.	5 years