KaraciğerNakli

Emiroğlu Remzi,MD

Florence Nightingale Hospital

Department of General Surgery and Organ Transplantation

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HCC

HCC Yaşam oranları

Llovett et al .Hepatology;1999

Sasan Roayaie et al.

Ann Surg Oncol 2013

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^{Schwartz M. et al. Gastroenterology. 2004}

Karaciğer nakli yapılan ilk hastalar

Milan Kriterleri�(1996)

HCC

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^{Schwartz M. et al. Gastroenterology. 2004}

Genel Bilgi

Kim WR. Am J Transplant. 2013

Jones PD. Minerva GastroenterolDietol. 2013

Annals of surgery.Volume 253,number 3,March 2013

888888888888888888888888888888888888889

Cure chance after resection and Transplantation

• Antonio Daniella Pinta. Annals of surgery:2018

Rezeksiyon ve Karaciğer Nakli sonrası Kür Şansı

European journal of surgical Oncology 50:2024

Morits Drefs.

• Changes of long term survival of resection and liver transplantation in Hepatocellular carcinoma through out the years: A meta Analysis

UCSF Kriterleri

• Single nodule ≤ 6.5cm
• 3 nodule ≤ 4.5cm (total ≤ 8cm)

^{Yao et al. Liver Transpl. 2002}

Extended Criterias for HCC

• Kevin Ka-Wan Chu. Expanding Indications for Liver Transplant: Tumor and Patient Factors.
• Gut and Liver 2020

• 2012-2023: 1538 KC Tx, 199 HCC (%13)

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HCC

78 Out of Milan

121 Within Milan

23 (29%) recurrence

23 (29.4%) ex (Akc Ca and HCC recurrence

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6 (4.9%) recurrence,

breast ca ve krc met

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22 (18%) ex (MI, Kolangit, CMW septisemia, stomach ca,, Lung ca

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2 Salvage tx

1 portal vein tumor trombosis

199 HCC

Local Ablation

Downstage

TAKE öncesi

TAKE sonrası

Son MR

66 yaşında erkek, HBV+HCC, MELD 17

HCC: 6,5x7,2cm ( Milan dışı)

AFP: 14,2 ng/mL

CT and PET-CT makrovasküler invazyon ve uzak organ met yok

TAKE sonrası 50% den fazla nekroz ve AFP le 4,1 ng/mL ye düştü

3 ay takip sonrası: yenitümör gelişimi ve AFP yüksekliği tespit edilmedi.

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Canli vericili nakil sonrası pataloji: Tek tümör >50% nekroz ve canlı tümör 2,1x2,3cm.

3,5 yıl takip sonrası greft fonksiyonel ve rekurrens saptanmadı.

TAKE öncesi

İkinci TAKE

SonMR

65 yaşında, HBV+HCC, MELD:14 HCC: 8,9x7,5cm( Milan dışı ) AFP: 9,2 ng/mL

CT ve PET-CT smakrovasküler invazyon ve uzak organ metastazı yok. İlk TAKE sonrası nekroz oranı 30%

İkinci TAKE sonrası nekroz oranı (>50%)

AFP: 2,2 ng/mL

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Oğlundan canlı vericili karaciğer nakli yapıldı.

3 yıl sonra kontrolü greft çalışıyor rekürrens saptanmadı.

Tedavi öncesi

SBRT sonrası

Şında erkek hasta, HCV + HCC,

HCC: 18X14 cm( UCSF dışı )

AFP: 3,7 ng/mL

MR: v.cava ve sol portal vene makro vasküler invazyon ama ekstra hepatik yayılım yok

Malin tromboz .Aralık 2020

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Şubat 2021 . 5 seans total dose 4000 cGy + sorafenib

Metni buraya yazın

Risk Faktörleri

• PET +

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• MVI

PVT

MVI Hastalar

• Takip : Ortalama 32 ay

MVI NÜKS

Barselona Klinik Karaciğer Kanser Sınıflaması

HCC > 3 cm

• Lezyon < 2 cm → RF ablasyon MW yeterli.
• Cerrahi kadar başarılı

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• Lezyon >2 cm < 3cm
• Multipl lezyon hepsi < 3 cm

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Rezeksiyon olmaz ise RF veya MW, TACE , EBRT→ TARE

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HCC > 3cm (T2 ve T3)

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• Karaciğer nakli → Rezeksiyon → Lokal Ablasyon

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• SBRT
• TARE
• TACE + SBRT
• TACE+ RF
• TACE+ İmmunoterapi

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Downstage HCC (UNOS)

• HCC tek lezyon < 5cm → RF, MW
• HCC tek lezyon 5.1 - 8 cm

2-3 lezyon en büyüğü < 5 cm

4-5 lezyon en büyüğü < 3 cm

• HCC tek lezyon > 8 cm → TARE,SBRT
• HCC büyük çok sayıda diffüz → İMMUNOTERAPİ ve/veya diğer sistemik tedaviler.

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TACE

Verici morbidite ve mortalite oranları

Verici ölümü 34

Sağ lob (1/200) 0.4%

Sol lob 0.1%

Nakil yapılan 4

Verici morbidite 23.9%

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Ölüm 0

İptal edilen verici 1

Safra kaçağı ve darlığı 7

Pnomoni 2

Yara yeri enfeksiyonu 4

Fıtık 3

Verici Morbidite %8.6

• Her yıl, HCC, CCA 841,000 hastaya yeni tanı konmakta ve dünya çapında yaklaşık 782,000 kişi ölmekte.
• Her yıl 1.8 milyon kişiye kolo-rektal kanser teşhisi konmakta ve tahminen bunların %50’sinde karaciğer metastazı gelişecektir. (CRLM).
• Bu tümörlerin cerrahi olarak temizlenmesi kür için en iyi şansı sunar: Ancak bunların çok az bir kısmı karaciğer rezeksiyon adayıdır.
• Karaciğer nakli kür şansı sunar: Nakil tümörleri en geniş rezeksiyon marjı ile temizlerken aynı zamanda procarcinogenic hepatic microenvironmentı uzaklaştırarak yeni tümör oluşma şansını azaltır
• 1996’dan beri, daha iyi hasta seçimi ve cerrahi tekniklerin gelişmesi ile ameliyat ve ameliyat sonrası ölümlerin azalması: Karaciğer naklini çeşitli karaciğer tümörlerinin tedavisinde etkili bir yöntem haline getirmiştir. Hepatoloji ve Onkolojideki diğer gelişmelerle beraber tıp alanında yeni bir konseptin doğmasına sebep olmuştur. TRANSPLANT ONCOLOGY

Mazzaferro V. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med.1996

Abreu P, EASL. Recent advances in liver transplantation for cancer: The future of transplant oncology. Journal of Hepatology, 2019

TRANSPLANT ONKOLOJİ

• Abreu P, EASL. Recent advances in liver transplantation for cancer: The future of transplant oncology. Journal of Hepatology, 2019

Transplant�Onkoloji

• Transplantasyon, Dahiliye, Onkolojinin birçok disiplinini kapsayan bir konseptir.

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• Transplant onkolojisinin kritik bileşenleri:
• Kanser cerrahisine transplant tekniklerinin uygulanması ile konvansiyonal cerrahi sınırlarının genişletilmesi .
• Tümör biyolojisi ile transplant immünolojisi arasındakiilişki
• Kanser immunogenomics ışığında genomics çalışmaları için uygun bir platform oluşturması

• Hibi T. What is transplant oncology? Surgery, 2019

Liquid Biopsy

Transplant Onkolojide Son Gelişmeler

Transplant Oncology and Perihilar CCA

• In the 1990s, LT for unresectable PhCCA resulted in unacceptably high recurrence rates
• With the use of potent neoadjuvant therapy, significantly improved outcomes was achieved (1,2)
• In 2005, Rea et al. (Mayo clinic):
• external beam radiation therapy (45 Gy) combined with 5-FU
• Thereafter, brachytherapy (iridium-192, 20–30 Gy) and oral capecitabine until LT.
• a staging operation to exclude nodal and extrahepatic metastases and local extension of disease
• In patients who underwent LT, the overall survival rate at 5 years exceeded 80%

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1.Sudan D.Radiochemotherapy and transplantation allow long-term survival for nonre- sectable hilar cholangiocarcinoma. Am J Transplant,2002

2. De Vreede. Prolonged disease-free survival after orthotopic liver transplanta- tion plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl . 2006

Transplant Oncology and Perihilar CCA

• The definition of “unresectable disease” is not universal.
• Mayo Clinic group defined as:
• bilateral invasion of second-order biliary radicals (ie, Bismuth type IV tumors),
• encasement of the main portal vein and unilateral segmental ductal extension with contralateral vascular encasement,
• insufficient hepatic reserve.
• Ebata et al (2018): 5-year survival rate of 53% in patients with Bismuth type IV PhCCA and pN0M0 disease who underwent resection. (Similar to that of patients with de novo cancer who underwent LT at Mayo Clinic)
• Etun et al. (2018): Patients who underwent transplant for PhCCA had improved overall survival compared with resection (3-year: 72% vs 33%; 5-year: 64% vs 18%; P < 0.001).
• Among patients who underwent resection for tumors <3 cm with lymph-node negative disease, and excluding PSC patients, transplant was still associated with improved OS (3-year: 54% vs 44%; 5-year: 54% vs 29%; P = 0.03).

• Ebata T . Surgical resection for Bismuth type IV perihilar cholangiocarcinoma. Br J Surg . 2018
• Etun CG. Transplantation Versus Resection for Hilar Cholangiocarcinoma. Annals of Surgery, 2018

PHCC

Unresectable PHCC

Breuer E.et al.Ann.Surg 2022

Breuer et al.Ann of Surg2022.

P=0,005

Resection 18,1%

LT; 49.9%

Neoadjuvant chemoradiation associated to LT MUST be considered in selected patients with unressectable pCCA

Resectable PHCC

Etun.Ann Surg 2018 May;267(5)

Kevin Ka-Wan Chu. Expanding Indications for Liver Transplant: Tumor and Patient Factors. Gut and Liver 2020

• Mazzeferro 1995-2010 42 tx patient compared with 46 nontx patient 5 and 10 year survival 97%-89% versus 51%-22%
• Moris et al, systematic review, 2017:1,216 records retrieved, 64 studies were finally considered eligible.

5-year overall survival after LT for locally advanced, unresectable NET: ranging from 50% to 70%

Recurrence rate at 5 years: ranging between 30% and 60%

• Good prognostic factors:
• Less than 50% liver involvement, Ki67 index < %20, complete excision of primary tm, durable disease 6 months, Age < 60,
• Non pancreatic(GIS) neuroendocrine tumor (NET) as the primary lesion

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Transplant Oncology and NETNr Metastases

• Moris D. Liver transplantation in patients with liver metastases from neuroendocrine tumors: A systematic review. Surgery . 2017

Several important but unanswered questions:

• How should we incorporate quickly emerging, nonoperative treatments that have changed the landscape of treatment particularly for pancreatic NET, such as chemotherapy, local ablative, angiographic liver directed therapies, peptide receptor radionuclide therapy (PRRT) and molecular-targeted agents, somatostatine analogues, antiangiogenic treatment with LT?
• What is an appropriate measurement outcome (overall versus recurrence free survival, time to progression, etc.) when comparing LT with other treatment modalities, given the slow- growing, indolent biology of most NETs?
• What defines unresectability? Or should we be providing trans- plants to the patients with resectable but bulky disease?

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Transplant Oncology and Neuroendocrine Liver Metastases

Shimata K. Liver transplantation for unresectable pancreatic neuroendocrine tumors with liver metastases in an era of transplant oncology. Gland Surg . 2018.

Treatment Options

• SECA study (2013); 21 patients with liver-only CRLM
• 6 weeks of neoadjuvant chemotherapy
• 5 years survival 60%, but 19/21 had recurrence in liver graft
• The improved outcomes and renewed interest in LT for unresectable CRLM depends on:
• more effective chemotherapy
• recent advances in imaging
• precise understanding of tumor bi- ology (eg, KRAS and BRAF mutation)
• better perioperative management of LT
• refinements in immunosuppres- sive regimen
• Trials conducted along these lines :
• SECA II (Norwegian) 5y ears survival 73%
• TRANSMET study (France)
• Toronto study (Canada)

Transplant Oncology and Colorectal Liver Metastases

Standardized patient selection

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Individualized therapy

30% improvement in survival

Recurrence after resection is 50-70% →half is at liver

Recurrence after Tx is 40% → 6.6% is at liver

Transplant Oncology and CCA

• Early attempts of LT alone as treatment of CCA resulted in disappointing results, with a 5-year survival of 23% to 30%. (1,2)
• Neoadjuvant therapy before LT has been shown to result in improved survival outcomes
• Mayo Clinic Group (2000); neoadj: combination of external beam and transcatheter radiation with 5-Flu
• Hong et al. identified the lack of neoadj. and adj. therapy as an independent predictor of tumor recurrence after LT for CCA

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• 1. Meyer CG, Liver transplantation for cholangiocarcinoma:results in 207 patients. Transplantation 2000
• 2. Robles R, Figueras J, Turrión VS, et al. Spanish experience in liver transplantation for hilar and peripheral cholangiocarcinoma Ann Surg 2004
• 3. Hong JC. Predictive index for tumor recurrence after liver transplantation for locally advanced intrahepatic and hilar cholangiocarcinoma. J Am Coll Surg 2011

ICCA

Transplant Oncology and Intrahepatic CCA

• LT for intrahepatic CCA (ICCA) has been contraindicated.
• Sapisochin et al.(2014); LT for “very early” ICCA (single tumor and up to 2 cm) in cirrhotic patients
• 5-year overall survival and recurrence rates; 73% and 0% in the Spanish cohort
• 5-year overall survival and recurrence rates; 65% and 18% in the international cohort
• Chiba University group(2015); successful downsizing chemotherapy for initially unresectable, locally advanced ICCA .
• Lunsford et al (2018); 6 high selected patients with locally advanced ICCA in a noncirrhotic liver
• gemcitabine/cisplatin-based neoadjuvant chemotherapy
• the overall and recurrence-free survival at 5 years were 83% and 50%, respectively

• 1. Sapisochin G. "Very early" intrahepatic cholangiocarcinoma in cirrhotic pa- tients: Should liver transplantation be reconsidered in these patients? Am J Transplant . 2014
• 2. Kato A. Downsizing chemotherapy for initially unresectable locally advanced biliary tract cancer patients treated with gemcitabine plus cisplatin combi- nation therapy followed by radical surgery. Ann Surg Oncol . 2015.
• 3. Lunsford KE. Liver transplantation for locally advanced intrahepatic cholangiocarcinoma treated with neoadjuvant therapy: A prospective case-series. Lancet Gastroenterol Hepatol . 2018

ICCA

Unresectable IHCC

Future Expectations