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CE: M.S.; ANNSURG-D-17-02099; Total nos of Pages: 3;
ANNSURG-D-17-02099
RESPONSE
Response: ‘‘Which is the
True Role of Bridging
Therapies for HCC Patients
Waiting for Liver
Transplantation?’’
Reply:
e very much appreciate the comments
of Drs Lai, Vitale, Rossi, Cillo,
and Lerut on behalf of the European Hepatocellular Cancer Liver Transplantation
(ErHeCaLT) Study Group regarding our
manuscript,1 examining the effect of pretransplant bridging locoregional therapy
(LRT) on recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT)
in patients within Milan criteria. By virtue of
examining outcomes in listed HCC patients
who actually received LT, the dataset from
our US Multicenter HCC Transplant Consortium (UMHTC) could only be expected to
assess the utility endpoint (ie, risk of post-LT
HCC recurrence). A thorough intention-totreat analysis, as Lai et al allude to, would
have allowed for a robust analysis of urgency
(ie, pre-LT outcome) and transplant benefit as
well; unfortunately, the UMHTC dataset does
not currently include the waitlist outcomes
for HCC patients who dropped out due to
tumor progression or otherwise did not
receive LT.
Nonetheless, the results from our
large, multicenter study add significantly to
the growing body of evidence that a static
HCC Model for End-stage Disease (MELD)
allocation policy based on tumor size and
number alone fails to take into consideration
dynamic evaluations of an individual’s tumor
biology that have been shown to significantly
impact waitlist dropout and post-LT HCC
recurrence. Our findings that an increasing
number of locoregional treatments (which
undoubtedly serves as a surrogate for radiographic assessments demonstrating persistent, progressive, or de novo lesions)
negatively affect recurrence outcomes is consistent with numerous studies identifying
radiographic and pathologic response to
LRT as important determinants of both waitlist dropout and post-LT recurrence.2– 4 To
this end, we are in complete agreement with
Dr Lai and colleagues that inclusion of
dynamic measures of tumor response must
be included in any HCC allocation policy.
W
Disclosure: The authors have no conflicts of interest to
declare.
Copyright ß 2017 Wolters Kluwer Health, Inc. All
rights reserved.
ISSN: 0003-4932/16/XXXX-0001
DOI: 10.1097/SLA.0000000000002577
TO THE
LETTER
However, several points need to be
clarified. While our UMHTC data unequivocally demonstrate the lowest risk of posttransplant HCC recurrence in recipients
achieving a complete pathologic response,
we are certainly not advocating for these
patients to be prioritized for liver transplantation. Rather, similar to the recent publication of Lai et al5 examining the intention-totreat survival benefit of LT, we are drawing
the parallel conclusion that HCC patients
requiring an increasing number of pretransplant LRT, which may be viewed as a surrogate for a poor radiographic response to LRT,
may have a low transplant benefit.
Along these lines, we disagree with the
statement that the US liver transplant selection policy for HCC patients allocates organs
to the ‘‘earliest first’’ (ie, patients with compensated cirrhosis and CR). In October of
2015, in an attempt to mitigate the overprioritization of HCC recipients compared
with non-HCC patients with end-stage liver
disease, the Organ Procurement and Transplantation Network (OPTN) instituted a 6month mandatory waiting period before
awarding MELD exception points, with capping of the MELD score at 34 for HCC
recipients.6 More recently, the OPTN Liver
and Intestinal Organ Transplantation Committee has approved the newest iteration of
the HCC allocation policy that will allow
MELD exception prioritization of HCC
recipients presenting with beyond OPTN
T2 criteria tumors (ie, beyond Milan criteria)
who demonstrate favorable response to LRT
and are ‘‘down-staged’’ to T2 criteria. Similarly, candidates within T2 criteria who have
serum alphafetoprotein (AFP) greater than
1000, who previously were automatically
awarded MELD exception points, will now
be required to demonstrate a reduction of
AFP to less than 500 after LRT before receiving exception points.7 In perhaps the most
liberal policy to maximize ‘‘transplant benefit’’ for patients with HCC, the UNOS Region
5 Board recently approved an HCC ‘‘allcomers’’ protocol, where patients who have
tumors of any size, provided there is no
vascular invasion and AFP <500, will be
given an opportunity to receive MELD
exception points if they are successfully
down-staged by LRT to within Milan criteria
and demonstrate stability for 6 months.8
Taken in aggregate, it is clear that US liver
allocation policy is actively adopting strategies to maximize transplant benefit for HCC
recipients that is not based on the ‘‘earliest
first’’, while preserving ‘‘equity’’ for noncancer patients awaiting LT.
Finally, we appreciate Lai et al’s concerns regarding the statistical validity of our
finding that locoregional treatment itself was
an independent predictor of post-transplant
Annals of Surgery Volume XX, Number XX, Month 2017
HCC recurrence in the subset of patients not
achieving a complete pathologic response.
This finding was unexpected, and quite
intriguing. We generally agree that the multivariable analysis performed does not necessarily guarantee a complete elimination of
the selection bias inherent to observational
study data. To alleviate this concern, we
performed an inverse probability of treatment
weighted (IPTW) multivariable survival
analysis, which we agree is the best methodology to evaluate the true effect of the locoregional treatment short of the gold-standard
randomized controlled trial. In brief, a logistic regression analysis was used to model the
probability of receiving LRT among patients
not achieving complete pathologic response
as a function of numerous potential confounders including age, sex, liver disease
etiology, MELD, neutrophil-lymphocyte
ratio, pretransplant AFP, pathologic maximum diameter, pathologic grade, vascular
invasion, and tumor stage. The propensity
score was the probability of receiving LRT
after conditioning on these covariates. Each
patient was assigned a weight corresponding
to the inverse of the propensity score under
the logistic model. Comparison of the propensity scores in treated and untreated
patients confirmed that there was sufficient
overlap in the propensity score to allow
proper adjustment. Comparison of all potential cofounders between HCC recipients with
and without LRT in both the original
(unweighted) and weighted sample confirmed that the propensity matching successfully balanced the 2 groups (Table 1).
Utilizing this propensity matching in the
weighted sample, our IPTW competing risk
Cox regression model found that the adjusted
hazard ratio for the effect of LRT on post-LT
recurrence was highly statistically significant
(hazard ratio 1.3089, 95% confidence interval 1.04–1.65, P ¼ 0.023), confirming our
initial findings reported in the manuscript.
Contrary to Lai et al’s assertion, our
UMHTC finding does not represent the ‘‘only
study’’ that implicates LRT as potentially
negatively impacting HCC outcomes. In a
recent study by Xu et al,9 examining 384
HCC LT recipients (268 having undergone
pre-LT LRT), the authors found a significantly elevated incidence of post-transplant
HCC recurrence in patients with treatmentinduced or spontaneous partial necrosis in the
explant (22.6%) compared with recipients
with no necrosis (5.2%) or complete necrosis
(6.1%; P < 0.001). Interestingly, these
increased recurrences, which were primarily
lymphatic metastases, were associated with
higher circulating plasma levels of the angiogenic factors VEGF-A and VEGF-C,
increased expression of VEGFR-2 and
VEGFR-3 in the peritumoral tissue, and
www.annalsofsurgery.com | 1
Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: M.S.; ANNSURG-D-17-02099; Total nos of Pages: 3;
ANNSURG-D-17-02099
Annals of Surgery Volume XX, Number XX, Month 2017
Response to the Letter
TABLE 1. Distribution of Covariates by LRT Before (Unweighted) and After (Weighted) Propensity Matching
Unweighted Analysis
Covariate
Age, yrs
Sex (male), %
Diagnosis, %
HBV
HCV
NASH
Cryptogenic
Alcohol
Autoimmune
PBC/PSC
Noncirrhotic HCC
Other
Lab MELD
NLR
Maximum pre-LT AFP
Immediate pre-LT AFP
Pathologic max diam, cm
Pathologic grade, %
Well
Moderate
Poor
Vascular invasion, %
None
Microvascular
Macrovascular
AJCC T stage, %
T1
T2
T3a
T3b
LRT (n ¼ 2082)
59 (54.1–64.0)
76.2
13
2.8
23.6
13.1
2.5
10.0
65.4
5.8
4.1
9.3
1.0
1.7
0.5
2.2
(9–18)
(1.8–4.7)
(8.7–123)
(5.5–44.2)
(1.9–3.5)
No LRT (n ¼ 711)
56 (52.0–62.0)
76.5
16
3.3
16.0
10.1
2.3
7.7
61.9
7.0
4.1
12.9
1.1
2.7
0.8
1.7
(12–23)
(2.0–6.0)
(6.3–65.0)
(5.0–45.7)
(1.8–3.1)
28.9
60.9
10.3
30.7
57.5
11.8
73.1
22.5
4.4
70.7
23.9
5.3
35.5
55.7
4.2
4.5
43.0
49.6
2.0
5.3
Weighted Analysis
LRT (n ¼ 2082)
P
<0.001
0.877
0.039
<0.001
<0.001
<0.001
0.154
<0.001
0.255
No LRT (n ¼ 711)
58.5 (54.0–63.0)
76.2
58.0 (53.0–64.0)
75.9
9.3
64.5
6.1
4.1
10.2
1.0
2.0
0.7
2.0
13.3
2.9
20.7
12.7
2.5
9.1
65.4
6.3
4.4
9.6
1.0
2.0
0.8
1.5
14.0
3.0
22.0
12.2
2.5
(10–19)
(1.8–4.9)
(8.0–107)
(5.3–42.2)
(1.8–3.5)
29.1
60.2
10.7
28.6
59.9
11.5
72.4
22.9
4.7
72.3
23.3
4.5
37.7
53.9
3.7
4.8
38.7
50.9
5.9
4.5
(10–18.4)
(1.9–5.0)
(7.5–98.6)
(5.2–53.0)
(1.9–3.5)
0.395
P
0.815
0.924
0.999
0.919
0.989
0.582
0.847
0.479
0.891
0.956
<0.001
0.234
Continuous variables summarized as medians and interquartile ranges.
AJCC indicates American Joint Committee on Cancer; HBV, hepatitis B virus; HCV, hepatitis C virus; NASH, nonalcoholic steatohepatitis; NLR, neutrophil lymphocyte ratio;
PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis.
increased immunofluorescent staining of
peritumoral lymphatics in patients with
tumor necrosis compared with patients without necrosis. This constellation of findings
supports the contention that LRT-related tissue injury may induce a local lymphangiogenic stimulus, which, in the absence of
complete tumor destruction, allows lymphatic invasion of any remaining viable
tumor cells. Ravaioli et al10 examined the
impact of TACE in LT recipients with a single
HCC, and found that partial necrosis of the
tumor after treatment was an independent
risk factor for post-LT HCC recurrence,
and was associated with low E-cadherin
expression, a protein whose down-regulation
has been implicated in tumor invasion and
metastasis.11 Thus, instead of attributing our
UMHTC findings to statistical artifact, there
is now enough collective evidence that
locoregional treatment itself may unmask
aggressive underlying tumor behavior in
the subset of HCC patients who do not
achieve the intended response of complete
tumor destruction. Our scientific community
should be compelled to further investigate the
2 | www.annalsofsurgery.com
biological mechanisms by which locoregional treatment alters the peritumoral
microenvironment and potentially facilitates
the lymphovascular spread of HCC.
Over the past 2 decades, our transplant
community has indeed seen a ‘‘revolution’’ in
the risk assessment and selection of HCC
patients for liver transplantation, with a clear
bias now in favor of important dynamic
measures of tumor biology over the static
features of size and number alone. Furthermore, significant advances in the molecular
pathogenesis of HCC have provided an accurate landscape of the genetic alterations
responsible for HCC tumor development
and progression. As a result, we are on the
cusp of finding the ‘‘holy grail’’ in LT for
HCC, namely, a constellation of radiologic,
serum, and molecular biomarkers that will
identify the patients who stand to gain the
most transplant benefit while preserving
excellent outcomes with the utilization of a
scarce donor resource.
Vatche G. Agopian, MD
Dumont-UCLA Liver Transplant and Cancer
ß
Centers, Department of Surgery, David
Geffen School of Medicine at UCLA,
Los Angeles, CA
vagopian@mednet.ucla.edu
William C. Chapman, MD
Section of Transplantation, Department of
Surgery, Washington University in St. Louis,
St. Louis, MO
Ronald W. Busuttil, MD PhD
Dumont-UCLA Liver Transplant and Cancer
Centers, Department of Surgery, David
Geffen School of Medicine at UCLA,
Los Angeles, CA
On behalf of the United States Multicenter
Hepatocellular Carcinoma Transplant
Consortium (UMHTC)
REFERENCES
1. Agopian VG, Harlander-Locke MP, Ruiz RM,
et al. Impact of pretransplant bridging locoregional therapy for patients with hepatocellular
carcinoma within Milan criteria undergoing liver
transplantation: analysis of 3601 patients from the
2017 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
CE: M.S.; ANNSURG-D-17-02099; Total nos of Pages: 3;
ANNSURG-D-17-02099
Annals of Surgery Volume XX, Number XX, Month 2017
US Multicenter HCC Transplant Consortium. Ann
Surg. 2017;266:525–535.
2. Lai Q, Avolio AW, Graziadei I, et al. Alphafetoprotein and modified response evaluation criteria in solid tumors progression after locoregional therapy as predictors of hepatocellular
cancer recurrence and death after transplantation.
Liver Transpl. 2013;19:1108–1118.
3. Lai Q, Nicolini D, Inostroza Nunez M, et al. A
novel prognostic index in patients with hepatocellular cancer waiting for liver transplantation:
Time-Radiological-response-Alpha-fetoproteinINflammation (TRAIN) score. Ann Surg. 2016;
264:787–796.
4. Agopian VG, Morshedi MM, McWilliams J,
et al. Complete pathologic response to pretransplant locoregional therapy for hepatocellular
carcinoma defines cancer cure after liver
ß
transplantation: analysis of 501 consecutively
treated patients. Ann Surg. 2015;262:536–545
[discussion 543–535].
5. Lai Q, Vitale A, Iesari S, et al. Intention-to-treat
survival benefit of liver transplantation in patients
with hepatocellular cancer. Hepatology. 2017.
doi: 10.1002/hep.29342 [Epub ahead of print].
6. Liver and Intestinal Organ Transplantation Committee ‘‘Capping the HCC Exception Score at 34’’
2014. Available at: http://optn.transplant.hrsa.gov/media/1140/policy_notice_12-2014.
Accessed October 6, 2017.
7. OPTN Liver and Intestinal Transplantation
Committee ‘‘HCC auto approval criteria
changes’’; 2017. Available at: https://optn.
transplant.hrsa.gov/governance/publiccomment/hcc-auto-approval-criteria-changes/.
Accessed October 6, 2017.
2017 Wolters Kluwer Health, Inc. All rights reserved.
Response to the Letter
8. UNOS Region 5 Fall Meeting Liver Breakout:
HCC ‘‘All-Comers’’ Protocol; 2017. Available
at: https://www.transplantpro.org/community/
regions/region-5/. Accessed October 6, 2017.
9. Xu M, Doyle MM, Banan B, et al. Neoadjuvant
locoregional therapy and recurrent hepatocellular
carcinoma after liver transplantation. J Am Coll
Surg. 2017;225:28–40.
10. Ravaioli M, Grazi GL, Ercolani G, et al. Partial
necrosis on hepatocellular carcinoma nodules
facilitates tumor recurrence after liver transplantation. Transplantation. 2004;78:1780–
1786.
11. Wei Y, Van Nhieu JT, Prigent S, et al.
Altered expression of E-cadherin in hepatocellular carcinoma: correlations with genetic
alterations, beta-catenin expression, and clinical features. Hepatology. 2002;36:692–701.
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