HCC [Hepatocellular carcinoma] needs either liver resection or liver transplant. Liver transplant in HCC is challenging in view of underlying cirrhosis as well as long waiting time for organ donors. Once HCC patient is kept on waiting list for organ donation, there is a high risk of tumor progression beyond liver transplant eligibility criteria. Such patients need bridging therapy for the control of tumour while they are on waitlist for organ donor. These bridging therapy helps to prevent tumour progression as well as down staging them to within the transplant criteria. Timing & method of bridging therapy for HCC patients on waitlist is critical in management of such patients.

1. WHEN & HOW TO BRIDGE
TO TRANSPLANT ?
DR NIKET MAYANK SHAH
MCH SURGICAL GASTROENTEROLOGY
SIR GANGARAM HOSPITAL NEW DELHI
APRIL 2022

2. INTRODUCTION

3.  ESLD or Advanced HCC – LTx is the only cure
 HCC – 2nd MCC in men & 6th MCC in women for cancer related mortality [1]
 HCC is the only solid organ tumor to be treated with liver transplant.
 5 year survival rate after LT for HCC – 60-70% [2]
 No.of HCC patients waiting for LT >>> Available organ donors
 Once in waitlist, the goals –
 To keep waiting time short
 To avoid drop-outs
 To avoid tumor progression

4.  Concept of Bridging Therapy
 Reducing the amount of viable tumor in liver improves post-LT survival
 No guidelines for the decision which patients should receive bridging therapy.
 AASLD – Bridging therapy to every patient who is expected to wait for more than 6 months for LT. [3]
 Best treatment option in Bridging therapy – remains unknown [4]

5. SELECTING HCC
PATIENTS FOR LT

6.  Curative treatment options for HCC
 Ablation
 Resection
 LT
 Resection
 HCC with background normal liver parenchyma
 5% of Western & 40% Asian patients [5]
 Up to 70% can be resected
 5 year survival 60-65% [6]

7.  LT
 HCC with an underlying cirrhosis
 Goals
 Complete removal of tumor & Undetected lesions
 Removal of cirrhotic liver
 Avoids risk of developing de-novo tumors in diseased cirrhotic liver
 Multiple criterias

8. [7]

9.  Currently no agreement on the selection of patients with advanced HCC for LT.
 Milan criterias – too strict excluding patients expected to have good outcomes after LT

10. WHO NEEDS
BRIDGING
THERAPY…

11.  % HCC patients will be removed from LT list due to tumor progression – 20-30% [8]
 Bridging therapy recommended for waiting time > 6 months for LT [9]
 Risk factors for drop outs from waiting list [10]
 1 tumor 3-5 cm
 2 or 3 tumors
 Lack of a complete response after 1st locoregional therapy
 High AFP after 1st locoregional therapy
 No randomized trials affecting the decision of type of bridging therapy
 Choice depends on center’s experience

12. HOW TO BRIDGE
…

13.  Local Treatment
 Resection
 TACE [Trans-Arterial ChemoEmbolization ]
 RFA [ RadioFrequency Ablation ]
 MWA [ MicroWave Ablation ]
 PEI [ Percutaneous Ethanol Injection ]
 SBRT [ Stereotactic Body RadioTherapy ]
 Systemic Treatment
 Sorafenib

14. BCLC staging for
HCC

16. LIVER
RESECTION [LR]

17.  Can be used theoretically as 1st line bridging procedure
 Theoretical advantages :
 Best possible control of tumor growth  TACE & Percutaneous treatments do not always achieve complete tumor
necrosis
 Pathological analysis of specimen & selecting patients with poor prognostic factors for immediate LT evaluation
 Dis-advantages
 Higher costs
 Peri-procedural risks
 Ensuing LT technically more difficult with higher post-operative complications

18.  Suitable patients
 Well preserved liver function / No cirrhosis
 Single exophytic / Subcapsular location tumors
 Left lobe tumors
 Salvage LT
 HCC within MC with preserved LFT  Can undergo Liver Resection
 If tumor recurrence / Liver function failure  Rescue LT
 Effective in both settings DDLT & LDLT
 Combination of prior recipient hepatectomy + a living donor graft provides excellent long term survival [11]
 Belghiti et al – Primary LT in cirrhotic V/S Secondary LT after initial LR [12]
 SIMILAR post-operative course, complications & 3 years & 5 years survival

19.  Unsuitable for salvage LT
 HCC recurrence overcoming conventional LT criteria
 Age >65 years at time of recurrence
 Severe comorbidities precluding LT

20. TACE
[TRANS-ARTERIAL CHEMO-EMBOLIZATION]

21.  Most commonly used modality for waitlist patients with low major complication rate.
 First line Treatment for BCLC intermediate stage HCC- BCLC stage B [13]
 Partial response – 15-55% Improvement in median survival - 16-20 months [14]
 2 types
 Conventional TACE
 DEB-TACE

22.  Conventional TACE
 Steps
1. Arterial infusion of lipiodol emulsion with chemotherapeutic agent [Doxorubicin/Cisplatin]
2. Embolization with gelfoam
 Disadvantages
 Require repetition either at regular intervals / at demands
 Damage to non-cancerous hepatocytes function
 Super selective TACE
 Recommended for WaitList patients
 To minimize ischemic injury to non-tumoural liver tissue

23.  Conventional TACE
 Limitation [15]
 Not a standardized procedure
 Optimal chemotherapeutic/embolization agent not yet determined
 Re-treatment strategy not yet determined

24.  DEB TACE
 Drug Eluding Beads [DEB]- particles of various size
 Able to bind & elute chemotherapeutic agent in a predictable manner [16]
 Advantages [17]
 More standardized approach
 Less liver related toxicity
 Less systemic adverse effects

25.  Tumor necrosis s/p TACE
 27-57% of complete tumor necrosis within MC [Milan Criteria] [18]
 Rate of necrosis higher [19]
 In Single nodule >> multiple nodules
 Super selective TACE >> Conventional/Lobar TACE [ 53.8% v/s 29.8% ]
 Nodules 3-5 cm >> Nodules < 3 cm
 Larger nodules are fed by larger arteries – Chemoembolization more effective [18]
 Small nodules lack fully developed arterial neo-angiogenesis

26.  Kwan et al [18]
 Pre-TACE angiogram
 Avid lesion enhancement
 Feeding vessel largen than 0.9mm diameter
 Post-TACE angiogram
 Lack of residual contrast enhancement
 Decrease in lesion size
 High density lesion due to an accumulation
 Diffuse distribution of ethiodized oil throughout the lesion
 Nicolini et al. - DEB-TACE v/s Conventional TACE [20]
77% v/s 27.2% tumor necrosis
>90% necrosis seen on explanted liver
Near complete lesion Necrosis

27. RFA
[Radio-Frequency Ablation]

28.  Small HCC not amenable to surgical resection.
 Small & early HCC with a diameter of <3 cm [21]
 Method
 Cool tip / hook needles
 Electrode placed percutaneously into targeted tissue
 Alternate current  Ionic frictions  High temperatures
 Rate of complete necrosis  Size HCC [22]
 Upto 3 cm  50-78%
 > 3 cm  13-43%
 Tumor > 3 cm  Independent risk factor for persistence of HCC after RFA treatment

29.  RFA related complications [23]
 Just 3-4%
 Acute cholecystitis
 Arterial Haemorrhage
 Biliary stenosis
 Small bowel perforation
 Tumor seeding at needle tract
 Major limitations [24]
 Proximity of tumor to biliary tree, gallbladder, caudate lobe & liver surface
 Proximity to major vessels  Heat sink effect

30. Other Percutaneous Options
-PEI [ Percutaneous Ethanol Injection ]
-PLA [ Percutaneous Laser Ablation ]
-MWA [ Microwave Laser Ablation ]
-TARE [ Trans-Arterial Radio-Embolization]
-CRT [ Conformal Radio-Therapy ]

31.  PEI
 Oldest treatment for localized HCC
 RARELY used as bridging
 One multinational survey - Rate of complete necrosis < 30% for tumors < 3 cm [25]
 PLA
 Multiple tiny laser fibres
 Tumor necrosis comparable to RFA
 Rate of necrosis in nodules upto 3 cm – 62%
 Advantages due to fine needles
 High risk sites [ near vital structures ]
 Severe clotting impairement
Where RFA is C/I

32.  MWA
 C/w RFA
 Larger area of necrosis
 Nodules in proximity to larger vessels can be treated [ No heat sink effect ]
 Promising role
 As a bridging procedure to LT
 As downstaging procedure in HCC patients

33.  TARE
 With 90Yttrium microspheres
 Riaz et al [26] – 38 HCC nodules in 35 patients
 T2 HCC – 15 patients  None progressed to T3 HCC before LT
 Stage T3 – 10 patients  [Downstaged]  Stage T2 – 8 patients
 Explant analysis – 61% complete tumor necrosis
 Necrosis depends on size of lesion
 < 3cm  89%
 3 – 5 cm  65%
 > 5cm  33%

34.  CRT
 Sandroussi C et al [27] – 5/6 fractions of RT to 10 patients of HCC on waitlist
 Well tolerated
 2 tumors remained stable
 8 tumors showed 10-50% regression
 LT in 5 patients
 Explant pathology – 40-90% tumor necrosis
 No recurrence at 6 months follow up
 Further studies needed

35. SYSTEMIC
TREATMENT
-SORAFENIB

36.  Multi kinase inhibitor acting as anti-angiogenic drug
 Vitale et al. [31] – Neoadjuvant sorafenib during WL v/s No bridging therapy
 Beneficial effect on survival
 Positive impact on transplant probability
 Extend time to progression
 Cost effective
 BUT..
 Evidence too small
 Need RCT for justification to use as bridging therapy
 Currently – Not recommended as standard therapy

37. COMBINED
TREATMENT

38.  Rationale
 To reach a higher local tumor control rate by higher rate of complete tumor necrosis
 RFA  TACE or TACE  RFA ?????
 RFA  Hyperemic rim surrounding ablation area  Consequently targeted by TACE more effectively
 TACE  Reduced heat sink effect  Larger ablation zones can be achieved with RFA
 Ashoori et al [28] – 44 HCC patients within MC – TACE  RFA
 76.9% rate of complete tumor necrosis in 16 patients with 26 nodules who underwent LT
 No major complications

39.  CRT
 Sandroussi C et al [27] – 5/6 fractions of RT to 10 patients of HCC on waitlist
 Well tolerated
 2 tumors remained stable
 8 tumors showed 10-50% regression
 LT in 5 patients
 Explant pathology – 40-90% tumor necrosis
 No recurrence at 6 months follow up
 Further studies needed

40. C/I
FOR BRIDGING
THERAPY

41.  Not recommended for waiting time < 6 months
 Decision of bridging therapy depends on…
 General health condition of patients
 Limitations & C/I for each method

42. CONTRA-INDICATIONS
 RFA
 Tumors within 1 cm of main biliary
tract
 IHBRD
 Bilio-enteric anastomosis
 Exophytic location of tumor
 Untreated coagulopathy
 TACE
 Decompensated cirrhosis [CTP B8 &
higher]
 Severely reduced portal vein flow
 Renal insufficiency
 Tumor size > 10cm
 Untreated varices at high risk of
bleeding
 Bile duct occlusion
 Severe co-morbidities
 TARE
 Lung shunting > 20%
 Estimated radiation doses for lung
 >30 Gy [single administration]
 >50 Gy [multiple administration]
 Uncorrectable flow to GIT
 CRT
 Lesions within 2 cm of bowel due
to GI toxicity

43. NUTSHELL

44. [29]

45. Multiple Studies on…
- Non surgical Bridging therapy for HCC

46. [29]

47. SCHEMATIC
OVERVIEW …

48. [30]

49. CONCLUSION

50.  T1 HCC – No evidence of benefits of bridging therapy [32]
 T2 HCC
 Waiting time < 6 months – no need of bridging therapy [32]
 Waiting time > 6 months – bridging therapy is strongly recommended [AASLD, EASLD] [32, 33, 34]
 Delay > 6-12 months without bridging therapy - Risk factor for… [8]
 Tumour progression
 Drop-out from waitlist
 Interval dissemination causing post LT recurrence
 Salvage LT
 In prior hepatectomy with tumor recurrence within transplant criteria
 In liver functional failure
 Similar results with DDLT & LDLT

51.  No recommendation for one type of locoregional therapy over others [32]
 < 3 cm  RFA
 > 3cm  TACE [ Selective/ Superselective >>> Conventional TACE ] [ DEB-TACE >>> Lipiodol TACE ]
 Smaller lesion at sites dangerous for RFA  PEI
 Multimodal treatment strategies [ Sequential TACE & RFA ]
 Response to neoadjuvant treatment assessment by mRECIST criteria by assessing…
 Amount of necrosis &
 Amount of residual tumour load

52.  Advantages of bridging therapy in T2 HCC
 Reduced drop out rate from waiting list
 Positive impact on post-LT HCC recurrence
 Positive impact on overall survival
 Response in Pre-LT  Surrogate marker of tumour biology
 Helpful in Selection & Prioritization of candidates for LT

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58. THANK YOU…