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Adjuvant therapy for Hepatocellular Cancer with orthotopic Liver transplantation''

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recurrence rates of HCC after liver transplant are disappointing, (though ... Gastroenterology. 1993 Jan;104(1):196-202. N=20, 17 pateients had tumor more than 5cm. ... – PowerPoint PPT presentation

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Title: Adjuvant therapy for Hepatocellular Cancer with orthotopic Liver transplantation''


1
Adjuvant therapy for Hepato-cellular Cancer with
orthotopic Liver transplantation..
2
Do we need to do something more for HCC
with/after Liver transplant?
3
Do we need to do something more for HCC after
Liver transplant?
  • recurrence rates of HCC after liver transplant
    are disappointing, (though improvement in
    outcomes are seen with better case selection)
    approx 5-year survival rates of 60-80 and
    recurrence free survival rates of 60-65 when
    selection criteria are strictly followed.

4
Do we need to do something more for HCC after
Liver transplant?
  • recurrence rates of HCC after liver transplant
    are disappointing (though improvement in outcomes
    are seen with better case selection).
  • accepted selection criteria include the Milan
    criteria and the UCSF criteria.
  • many patients do not meet the selection
    criteria.

5
Do we need to do something more for HCC after
Liver transplant?
  • recurrence rates of HCC after liver transplant
    are disappointing (though improvement in outcomes
    are seen with better case selection).
  • accepted selection criteria include the Milan
    criteria and the UCSF criteria.
  • many patients do not meet the selection
    criteria.
  • with LDLT, the demand for liver transplantation
    for HCC is probably increased, and there has been
    an attempt to extend selection criteria beyond
    existing ones.

6
Do we need to do something more for HCC after
Liver transplant?
  • recurrence rates of HCC after liver transplant
    are disappointing (though improvement in outcomes
    are seen with better case selection).
  • accepted selection criteria include the Milan
    criteria and the UCSF criteria.
  • many patients do not meet the selection
    criteria.
  • with LDLT, the demand for liver transplantation
    for HCC is probably increased, and many times
    selection criteria have been extended.
  • Hepatic and/or extra-hepatic recurrence of the
    HCC obviously reduces the effectiveness of the
    treatment option, and also is not acceptable in
    terms of cost effectiveness.

7
What adjuvant therapy?
  • Pre-transplant adjuvant therapy in the form of
    TACE
  • (trans arterial chemo-embolization, or RFA
    (radio-
  • frequency ablation) or PEI (per-cutaneous
    ethanol
  • injection).
  • Intra-operative adjuvant therapy, viz
    intra-operative
  • chemotherapy.
  • Post transplant adjuvant systemic chemotherapy.

8
Why (on what basis) will any adjuvant therapy be
useful?
9
Is transplantation truly superior to resection
for HCC in cirrhotics?Ann Surg. 2007 January
245(1) 5158.Poon and others (HK). .. Diff in
Tumor Invasiveness in Cirrhotic Patients With HCC
Fulfilling the Milan Criteria Treated by Resectn
and Tx. (n240)
  • Tumors in the transplanted group were associated
    with lower incidence of high-grade tumors,
    microscopic venous invasion, and microsatellite
    nodules. The overall 5-year survival was better
    in the transplantation group than the resection
    group (81 vs. 68, P 0.017). However, there
    were no significant differences in survival
    between the two groups when stratified according
    to presence or absence of venous invasion.
  • There were significant differences in tumor
    invasiveness in HCC treated by transplantation
    and resection as a result of selection bias, even
    in patients with the tumors fulfilling the Milan
    criteria. When the different tumor invasiveness
    was taken into account, there was no significant
    difference in the long-term survival after
    resection or transplantation.

10
Biological basis for the use of adjuvant
chemotherapy in the setting of Liver tx for HCC
  • Cancer cells may be found in the blood of the
    right atrium, portal vein and peripheral
    circulation during hepatectomy.
  • (this has also been reported to occur during
    standard liver resection/ recipient hepatectomy
    for liver tumours)
  • Micro-metastatic disease may already exist
    preoperatively or disseminate iatro-genically
    during OLT.
  • HCC is moderately chemo-sensitive, and adjuvant
    chemotherapy may be used without significant
    adverse effects on the outcome.

11
Wong IH, Lau WY, Leung T, Yeo W, Johnson
PJ.Hematogenous dissemination of hepatocytes and
tumor cells after surgical resection of
hepatocellular carcinoma a quantitative
analysis.Clin Cancer Res. 1999 Dec5(12)4021-7.
  • showed significantly raised afp mRNA levels in
    postoperative peripheral blood from 9 of 13 HCC
    patients (70), among which P3 and P4 showed the
    clearance of afp mRNA afterward. As a result,
    seven patients were identified to be at high risk
    for recurrence or metastasis. Indeed, five of
    these seven patients (72) who showed
    persistently elevated afp mRNA levels died from
    lung metastasis, liver recurrence, or persistent
    HCC with intrahepatic metastasis within 1 year
    after surgery.
  • 80 (four of five) of relapse took place in the
    liver, a particularly fertile ground for HCC
    cells to proliferate. In accordance with Pagets
    "seed and soil" hypothesis, the disseminating
    capacity of tumor cells rather than the local
    outgrowth is controlled by the "soil"
    characteristic.

12
S. Marubashi, , K. Dono, Y. Sugita,and others..
(Japan, Osaka Univ.). Transplantation
Proceedings Volume 38, Issue 10, December 2006,
Pages 3640-3642(n25 patients who underwent LDLT
for HCC with underlying cirrhosis.)
  • In the patients with HCC exceeding Milan criteria
    (n 15), the presence of AFP mRNA-positive cells
    in the peripheral blood correlated significantly
    with HCC recurrence (P .033). We concluded that
    the presence of AFP mRNA-expressing cells could
    be a useful predictor of HCC recurrence in liver
    transplant patients.
  • Univariate analyses of the risk factors for HCC
    recurrence using the log-rank test showed that
    the presence of AFP mRNA-positive cells in the
    peripheral blood correlated with HCC recurrence
    both at the peri-operative and pre-operative
    periods (P .037 and .007, respectively).
    Microscopic vascular invasion was also associated
    with HCC recurrence (P .005).

13
Stone MJ, Klintmalm GB, Polter D, Husberg BS,
Mennel RG, Ramsay MA, Flemens ER, Goldstein
RM.Neoadjuvant chemotherapy and liver
transplantation for hepatocellular carcinoma a
pilot study in 20 patients.Gastroenterology.
1993 Jan104(1)196-202.
  • N20, 17 pateients had tumor more than 5cm.
  • Doxorubicin was administered preoperatively,
    intraoperatively, and postoperatively at a dose
    of 10 mg/m2 weekly, totaling 200 mg/m2.
  • Eight patients died, five of recurrent tumor and
    three of hepatitis B. Three others remain alive
    8-22 months after tumor recurrence. One patient
    had initial tumor recurrence in the allograft.
    Actuarial survival is 59 and tumor-free survival
    is 54 at 3 years. For the 17 patients with
    tumors gt 5 cm, overall survival is 63 and
    tumor-free survival is 49 at 3 years.

14
ZHOU Jian, TANG Zhao-you, and others...Liver
transplantation for patients with hepatocellular
carcinoma at the Liver Cancer Institute of Fudan
University, China.Chinese Medical Journal, 2005,
Vol. 118 No. 8 654-659
  • 65 patients accepted 1-6 cycles (mean 3.1
    cycles) of systemic chemotherapy when the results
    of liver, kidney, blood routine tests (21-58 days
    after transplantation, mean 28 days) were within
    normal limits and their general conditions were
    good.
  • A 3-day chemotherapeutic regimen was prescribed
    with intravenous fluorodeoxyuridine (FuDR) 300
    mg/m2 qd for 3 days, cisplatin 20 mg/m2 qd for 2
    days, and doxorubicin 20 mg/m2 on the first and
    the third day. ChemoRx repeated at an interval of
    1 month.
  • Postoperative chemo-therapy, early cessation of
    prednisolone and reduction of long-term
    immunosuppressive drugs may reduce the risk of
    tumor recurrence in patients with HCC after OLT.
  • 1- and 2- year cumulative survival rates were
    90.0 and 65.6, and their disease-free survival
    (DFS) rates 77.5 and 62.5, respectively.

15
N J De La Revilla, et al.Transplantation
Proceedings Usefulness of chemotherapy as
prophylaxis of tumor recurrence after liver
transplantation in advanced hepatocellular
carcinomas.Volume 35, Issue 5, August 2003,
Pages 1830-1831
  • N10 patients with aggressive HCC, exceeding the
    Milan criteria.
  • The chemotherapy regimen used adriamycin (20
    mg/m2 weekly for 20 weeks). Six patients were
    stage IVA and four stage III.
  • Disease-free survival rates were 83 in patients
    with well-differentiated hepatocellular carcinoma
    at 3 yr and 25 in those with moderately
    differentiated hepatocellular carcinoma.
    Tolerance of chemotherapy was good.
  • The use of adriamycin in patients undergoing
    liver transplant due to advanced hepatocellular
    carcinoma may be useful to prevent tumor
    recurrence it is well tolerated. The presence of
    vascular tumor invasion and a lower grade of
    histologic differentiation were associated with a
    poor prognosis.

16
Pre transplant adjuvant therapy-
  • AIM OF NEO-ADJUVANT THERAPY
  • Downstage the tumour?
  • Waiting for a cadaveric transplant.
  • Extension of criteria used to allocate livers..?
  • Truly adjuvant. i.e. therapeutic to improve
    outcomes of Liver transplantation.

17
U. Cillo, A. Vitale, and others (2007)
Intention-to-Treat Analysis of Liver
Transplantation in Selected, Aggressively Treated
HCC Patients Exceeding the Milan Criteria.
American Journal of Transplantation 7 (4),
972981.
  • Aggressive pre-op adjuvant therapy was given, as
    a bridge to liver transplantation. All tumours
    were biopsied, and tumours with poor
    differentiation were excluded from the list.
  • N100.
  • Neo-adjuvant treatments used
  • 1. RFA.
  • 2. PEI (used for smaller lesions, and also
    lesions close to vascular structures.
  • 3. TACE (multi-focal tumours, without vascular
    anomalies, and moderately well preserved liver
    function).
  • 4. n100, of which 40 patients exceeded Milan
    criteria of which 68 underwent liver
    transplants. The remaining were either excluded,
    or developed progression of disease, or had no
    biopsy, or are still awaiting transplant.

18
  • The Milan criteria did not prove to be a
    significant predictor of dropout probability or
    survival rates using Cox's analysis. Cumulative
    dropout probability at 6 and 12 months was 0 and
    4 for MILAN OUT, and 6 and 11 for MILAN IN.
    The intention-to-treat survival rates at 1 and 3
    years were 95 and 85 in MILAN OUT, and 84 and
    69 in MILAN IN. None of the 68 transplanted
    patients had recurrent HCC after a median
    16-month follow-up (069 months). In conclusion,
    LT may be effective for selected,
    aggressively-treated HCC patients exceeding the
    Milan criteria.

19
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20
Role of pre-transplant TACE survival
advantage?
-Bridge to transplant?
  • In conclusion, TACE followed by OLT is associated
    with an excellent outcome in selected patients.
    Furthermore, TACE is highly efficacious in
    preventing tumor progression while waiting for
    OLT. Although TACE reduced tumor preoperatively,
    it failed to show a beneficial effect on patient
    survival in advanced-stage HCCs. (n48) Liver
    Transplantation 2003 Volume 9, Issue 6 , Pages
    557 563. IW Graziadei et al, Innsbruck.
  • In conclusion, successful tumor downstaging can
    be achieved in the majority of carefully selected
    patients, but longer follow-up is needed to
    further access the risk of HCC recurrence after
    OLT. (n16) A prospective study on downstaging
    of hepatocellular carcinoma prior to liver
    transplantation. Yao et al Liver Transpl. 2005
    Dec11(12)1505-14.

21
  • TACE therapy of the HCC before liver
    transplantationexperiences. Rofo. 2005
    May177(5)681-90. (German) Herber et al... The
    sequential TACE is an effective method for the
    therapy of the HCC before LTx in selected
    patients. A relevant downsizing could be achieved
    by TACE in patients with advanced HCC. Patients
    with larger tumors showed a significantly
    stronger size reduction after TACE. The
    recurrence rate and the survival rate for
    patients with advanced or small tumors do not
    differ.

22
..
  • Influence of preoperative transarterial lipiodol
    chemoembolization on resection and
    transplantation for hepatocellular carcinoma in
    patients with cirrhosis. Majno PE et al. Ann
    Surg. 1997 Dec226(6)688-701. Downstaging or
    total necrosis of the tumor with TACE occurred in
    62 of the cases and was associated with improved
    disease-free survival both after liver resection
    and transplantation. In liver resection, TACE was
    also useful to improve the resectability of
    primarily unresectable tumors. In liver
    transplantation, downstaging in patients with
    tumors gt3 cm was associated with survival similar
    to that in patients with less extensive disease.
    (n49/76 for resection and 54/111 for transp.)

23
Efficacy of RFA -
  • In conclusion, percutaneous RFA is an effective
    bridge to OLT for patients with compensated liver
    function and safely accessible tumors.
    Tumor-related dropout rate and post-OLT outcome
    compared favorably with published controls of
    patients with early-stage disease. This can be
    attributed to the efficacy of RFA in producing
    local cure or curbing tumor progression during
    the waiting period. Hepatology. 2005
    May41(5)1130-7, Lu DS et al..
  • RFA is a safe and effective treatment of small
    HCC in cirrhotics awaiting OLT, although tumor
    size (gt3 cm) and time from treatment (gt1 year)
    predict a high risk of tumor persistence in the
    targeted nodule. Ann Surg. 2004
    Nov240(5)900-9, Mazzaferro and others..
  • In summary, our data show that RFA is a safe and
    effective treatment modality for patients with
    advanced cirrhosis and nonresectable HCC. The
    ability of RFA to prevent or delay tumor
    progression needs analysis, its favorable safety
    profile and promising efficacy make it an
    attractive treatment option for transplant
    candidates with unresectable HCC. Liver Transpl.
    2002 Dec8(12)1165-74, Fontana et al

24
Percutaneous ethanol injection-
  • Often used for liver tumours lt3cm or 3cm
  • Most often used when the liver condition itself
    precludes resection.
  • Of late has been used with RFA and TACE with
    probably superior results.
  • Combination treatments are used when the lesion
    is not completely accessible or tumour size is
    larger.
  • PEI seems to be safer when the lesions are
    situated close to large vascular structures/
    important structures.
  • Attractive option to reduce the size of the
    tumour when waiting for Liver Tx.

25
Efficacy of pre transplant ablative therapy in
inducing tumour necrosis
  • Efficacy of hepatocellular carcinoma locoregional
    therapies on patients waiting for liver
    transplantation. Moreno and others. (Spain)
    Transplant Proc. 2005 Apr37(3)1484-5. (n13)
  • Most patients with solitary nodules lt4 cm who
    received PEI had 90 to 100 tumor necrosis.
    Larger tumors had 25 to 30 necrosis. TACE was
    employed in six patients with large and/or
    multiple tumors, obtaining 20 to 50 tumor
    necrosis. RFA was employed in one case obtaining
    85 necrosis (tumor of 4 cm). No serious
    complications occurred with any technique.
    According to our experience, PEI and RFA are
    effective locoregional therapies to treat
    hepatocellular carcinomas of lt4 cm in patients on
    the waiting list. For larger tumors, their
    association with other techniques, such as TACE,
    seems adequate.

26
However ..
  • (Retro-spective case control study, n100 in each
    group.) Impact of pretransplantation
    transarterial chemoembolization on survival and
    recurrence after liver transplantation for
    hepatocellular carcinoma. Liver Transpl. 2005
    11(7)767-75. Decaens T et al. (France). In the
    TACE group, 30 patients had tumor necrosis gt or
    80 on the liver explant with a 5-year survival
    rate of 63.2, compared with 54.2 among their
    matched controls (P 0.9). In conclusion, with a
    mean waiting period of 4.2 months and 1 TACE
    procedure, pre-LT TACE does not influence post-LT
    overall survival and disease-free survival.
  • (n21 in each group, retro spective case control)
    Arterial chemoembolization before liver
    transplantation in patients with hepatocellular
    carcinoma marked tumor necrosis, but no survival
    benefit? Oldhafer KJ et al.. J Hepatol. 1998
    Dec29(6)953-9.
  • Although preoperative chemoembolization or
    chemotherapy induced marked tumor necrosis, these
    patients showed no benefit in survival compared
    to historical controls.

27
What if we combine adjuvant treatments. i.e.
very aggressive adjuvant therapy?
28
Multi-modality adjuvant therapy for HCC with
Liver Transplantation
  • Ann Surg. 2002 April 235(4) 533539. Long-Term
    Results With Multimodal Adjuvant Therapy and
    Liver Transplantation for the Treatment of
    Hepatocellular Carcinomas Larger Than 5
    Centimeters. Sasan Roayaie et al. (NY.) n43. HCC
    gt 5 cm were selected.
  • Pre-operatively sub-selective TACE given with
    mitomycin C, doxorubicin and cis-platin.
  • Single intra-operative dose of doxorubicin (10
    mg/sq.m at the time of re-vascularisation of the
    graft.
  • systemic doxorubicin (50 mg/m2) every 3 weeks as
    tolerated, for a total of six cycles, beginning
    on the sixth postoperative week.
  • A significant proportion of patients with HCC
    measuring 5 cm or larger can achieve long-term
    survival after liver transplantation in the
    context of multimodal adjuvant therapy. Patients
    with tumors measuring 5 to 7 cm have
    significantly longer recurrence-free survival
    compared with those with larger tumors. RFS at 5
    years 55 v/s 34 in those with larger tumours.

29
  • Cherqui D, Piedbois P, et al.
    Multimodal
    adjuvant treatment and liver transplantation for
    advanced hepatocellular carcinoma. A pilot study.
    Cancer.
    1994 Jun 173(11)2721-6.
  • (n9, pros. study, 3yr actuarial survival 64.
    All exceeded UCSF criteria)
  • Conclusions- These results show that an
    aggressive adjuvant therapy can be used in
    association with liver transplantation in the
    treatment of advanced hepatocellular carcinoma
    without increased mortality and suggest that such
    a protocol could be effective in preventing tumor
    recurrence.
  • The treatment consisted of preoperative hepatic
    arterial chemo-embolization (iodized oil,
    doxorubicin, and gelatin sponge) and radiotherapy
    (5 Gy in one fraction immediately before
    surgery), and postoperative systemic chemotherapy
    with mitoxantrone.

30
Chemotherapy for recurrent disease
31
What agents for chemotherapy?
  • Doxorubicin (Adriamycin)
  • Cis-platin/ carbo-platin.
  • Capecitabine, gemcitabine, and 5-FU.
  • Interferon/ bevacizumab.
  • Mitoxanrone.
  • Sorafenib.
  • A combination of drugs is often used a platin
    with doxorubicin is the most favoured
    combination. Recently a combination of
    Gemcitabine and Oxaliplatin (GEMOX) with
    Bevacizumab has been quite promosing with 48
    progression free survival at 6 mths.
  • However, no survival advantage has yet been
    demonstrated with ChemoTh for recurrent disease.
    Hence the need for adjuvant therapy ....

32
However, caution is warranted..
  • Is there really a benefit?
  • 1. At this stage numbers are probably too
    small.
  • 2. Impact on viral hepatitis recurrence?
  • 3. Effect on cost-effectiveness.?
  • Post-OLT adjuvant chemotherapy does not avoid
    tumor recurrence and its fatal consequences but
    may contribute to prolonged tumor-free survival
    among a significant proportion of patients with
    high-risk HCC. However, the uncertain
    implications on viral recurrence and the lack of
    control groups do not allow post-OLT chemotherapy
    to be recommended outside controlled clinical
    trials, which are clearly warranted. (n46)
    (Transplantation Proceedings E. Bernal others
    Volume 38, Issue 8, October 2006, Pages
    2495-2498).

33
M Basanello and others., Adjuvant chemotherapy
for transplanted hepatocellular carcinoma
patients impact on survival or HCV recurrence
timing.Volume 35, Issue 8, Pages 2991-2994
(December 2003).
  • N48 pts underwent LTx, with HCC, among which 15
    pts had HCC detected only after explant
    histology.
  • One-, 3-, and 5-year overall survival rates were
    100, 85, 79 (CT group), and 89, 71, 71 (no
    CT group), respectively. The HCV recurrence-free
    survival at 3, 6, and 12 months was 29, 14, 0
    for the CT group, versus 76, 38, 25 for the no
    CT group (P .005).
  • Conclusions- Discontinuation of chemoRx in
    HCV-HCC patients after transplantation appears
    rational due to the early hepatitis C recurrence
    confirmed in our series. Moreover, few studies
    have demonstrated that CT prolongs survival of
    HCC transplanted patients. New pharmacological
    approaches are necessary to solve these
    questions.

34
To Conclude..
  • Adjuvant therapy may be useful, but when to use
    and what to use. remains a point of contention.
  • The optimal adjuvant therapy, or the combination
    of treatments, and the sequence in which to use,
    remain ill-defined.
  • Pre-transplant TACE/ RFA is useful to prevent
    progression of disease, but does not confer a
    survival advantage.
  • Peri-operative chemotherapy and adjuvant
    chemotherapy may be useful to prevent recurrent
    HCC, but effect on viral (HBV HCV) relapse
    rates might prove detrimental.
  • Rapid withdrawal of steroids is probably useful
    in lowering recurrence.
  • Case selection is probably the most important
    parameter, with poorly differentiated tumors and
    tumors with microscopic and macroscopic vascular
    invasion having high recurrence. Circulating
    peri-operative AFP-mRNA levels might be able to
    predict high risk subjects.

35
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