As the incidence of hepatocellular carcinoma (HCC) increases and some traditional indications (eg, hepatitis C virus cirrhosis) decline, HCC is becoming a more frequent cause for liver transplantation worldwide. Overall, results following transplantation in well-selected patients are good, with 5-year survival >70%.1 Nonetheless, posttransplant HCC recurrence continues to arise in approximately 16% of patients, and median survival following recurrence is typically <12 months.2,3 Some patterns of recurrence, such as focal lesions in the transplant allograft or lungs, may permit treatment with local resection or ablation, but a relatively small proportion of cases (<10%–30% of recurrences) are amenable to such curative-intent therapies, with ultimate cure of recurrence achieved in only about 1% of the entire HCC transplant population.4,5 The remaining majority of recurrences, including to the bone, brain, or multiple sites, can only be palliated.
Posttransplant surveillance has been proposed as a means to detect HCC recurrences in a latent phase, before they become overtly symptomatic and might still be amenable to local therapies. While there is evidence that primary HCC surveillance may lead to cost and survival benefits in patients with chronic liver disease,6 the case for posttransplant HCC surveillance remains unclear. Unlike primary HCC surveillance, which is typically done using ultrasound and limited to the liver where primary tumors invariably arise, posttransplant surveillance cannot be limited to a single organ or region, as all forms of recurrence are inherently metastatic disease. Screening tools that are more expensive, less well tolerated, and have the potential to be injurious (eg, due to the effects of ionizing radiation and intravenous contrast) have to be used to survey at least the most common sites. Currently, there is no data from any prospective clinical trial that may be used to guide the recommendation of a posttransplant HCC surveillance protocol, though expert opinion recommends multiphase contrast-enhanced computed tomography or MRI of the abdomen and computed tomography of the chest be performed every 6 months for 2–3 years.7
In this issue of Transplantation, Lee et al8 report the results of a retrospective analysis of data from 3 North American centers performed to determine if surveillance monitoring may have led to improved outcomes among patients with posttransplant HCC recurrence. Typical patients at the different centers underwent contrast-enhanced cross-sectional imaging of the chest and abdomen with or without bone scan 4× in the first 2 years. During follow-up, recurrence was detected in 223 among 1764 patients transplanted for HCC (13%): 165 through surveillance (74%) and the remaining 26% on imaging performed for other indications. The authors of the study introduce the novel concept of cumulative exposure to surveillance (CETS) and assigned 90 days to each surveillance imaging, based on theoretical tumor doubling times and the idea that a protective interval is offered in the period following each negative scan. Following multivariate regression analysis, they found that increasing CETS correlated directly with postrecurrence survival, even when adjusting for other risk factors, including treatment of recurrence with resection or ablation. They ultimately suggest that 252 days of CETS should be performed during the first 2 years (the equivalent of 3 surveillance scans or 1 roughly every 8 months) to be able to offer potentially curative therapy.
While Lee et al8 suggest that increasing the number of posttransplant HCC surveillance scans can lead to better postrecurrence survival, one would expect this to be true if detection were to directly lead to treatment, as a scan itself is not therapeutic. The fact that an increasing number of scans (expressed as CETS) were significantly associated with postrecurrence survival independent of therapy indicates that: (1) increasing surveillance was a byproduct of less aggressive tumor biology, as even untreated recurrences progressed less rapidly to patient death, and (2) less aggressive lesions with a longer preclinical period and inherently better outcomes were more likely to be detected on surveillance imaging than rapidly lethal ones (length time bias). Comparing patients in this study with fewer as opposed to ≥252 days of CETS during the first 2 years, the former group had more aggressive disease at baseline (more Risk Estimation of Tumor REcurrence After Transplant (RETREAT) scores ≥5)9 and more aggressive recurrences arising earlier after transplantation and were less amenable to not only potentially curative therapy but repeated sessions of therapy in general. Overall, these results indicate that more aggressive HCC tumor biology leads to more rapid recurrence that will consequentially limit the amount of posttransplantation surveillance that can be performed as well as the likelihood that curative-intent therapy can be applied.
The Lee et al8 study evaluates a population including only patients with posttransplant HCC recurrence. It is plausible that the purported benefits of posttransplant surveillance in a broader population of HCC patients undergoing liver transplantation for HCC, the majority (80%–90%) of which will never experience recurrence, will be less. A recent study from Liu et al3 evaluated the benefits of posttransplant surveillance with cross-sectional imaging of the abdomen and chest performed every 3 months for 5 years and every 6 months thereafter. Posttransplant HCC recurrence was detected in 24 of 125 patients (19%): 11% within 2 years, another 7% by 5 years, and <1% thereafter. Using parametric frailty models, the authors did not detect differences in recurrence-free survival times between 3-month surveillance intervals all the way up to 12-month intervals. As well, among the 24 recurrences in the study, all but 1 underwent additional therapy, yet median postrecurrence survival despite therapy was only 14 months.3
There is an ongoing need for prospective clinical trials to adequately assess potential for posttransplant HCC surveillance to increase recipient longevity and at what cost. In the future, novel tools or biomarkers might help risk-stratify HCC patients, to perform targeted surveillance or avoid transplantation in high-risk patients. In the meantime, using current strategies, increasing HCC surveillance monitoring may be identifying different underlying tumor biology rather than providing an actual mechanism for improving posttransplant survival.
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2. de’Angelis N, Landi F, Carra MC, et al. Managements of recurrent hepatocellular carcinoma after liver transplantation: a systematic review. World J Gastroenterol. 2015; 21:11185–11198
3. Liu D, Chan AC, Fong DY, et al. Evidence-based surveillance imaging schedule after liver transplantation for hepatocellular carcinoma recurrence. Transplantation. 2017; 101:107–111
4. Roberts JP. Tumor surveillance-what can and should be done? Screening for recurrence of hepatocellular carcinoma after liver transplantation. Liver Transpl. 2005; 11Suppl 2S45–S46
5. Sapisochin G, Goldaracena N, Astete S, et al. Benefit of treating hepatocellular carcinoma recurrence after liver transplantation and analysis of prognostic factors for survival in a large Euro-American series. Ann Surg Oncol. 2015; 22:2286–2294
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7. Verna EC, Patel YA, Aggarwal A, et al. Liver transplantation for hepatocellular carcinoma: management after the transplant. Am J Transplant. 2020; 20:333–347
8. Lee D, Sapisochin G, Mehta N, et al. Surveillance for HCC after liver transplantation: increased monitoring may yield aggressive treatment options and improved postrecurrence survival. Transplantation. 2020; 140:2105–2112
9. Mehta N, Heimbach J, Harnois DM, et al. Validation of a risk estimation of tumor recurrence after transplant (RETREAT) score for hepatocellular carcinoma recurrence after liver transplant. JAMA Oncol. 2017; 3:493–500