Can Sorafenib Increase Survival for Recurrent Hepatocellular Carcinoma after Liver Transplantation? A Pilot Study
By Kemmer, Nyingi | |
Proquest LLC |
Recurrence of hepatocellular carcinoma (HCC) remains a main detriment to long-term survival in liver transplants (LTx) for HCC. The study aims to review the use of sorafenib in recurrent HCC LTx in the Model End Stage Liver Disease era. Two hundred forty-seven patients with HCC LTx from 2002 to 2013 were included. Survival was calculated by the Kaplan-Meier (KM) method and Cox multivariate model. Twenty-two patients recurred (11%). By KM, overall survival was 27 months (standard deviation [SD], 3.2 months; median, 28.4 months). Mean time to recurrence was 16.9 months (SD, 2.8 months; median, 12 months). Nine patients were treated with sorafenib after recurrence. Median survival for sorafenib-treated patients was 42 months compared with a median of 16.2 months without sorafenib (-2 log likelihood ratio, P = 0.0582). By Cox, only sorafenib (P = 0.0233; hazard ratio, 8.528) and pathologic stage had a significant impact on survival. The recurrence rates of HCC LTx remain acceptable considering understaging and expansion of beyond Stage A. This pilot study of sorafenib in recurrent HCC demonstrates improved survival over historic controls. Many other factors affecting improved survival are explained. However, treatment remains palliative. Quality-of-life years and cost analysis need to be performed in this population.
H EPATOCELLULAR CARCINOMA (HCC) REPRESENTS an increasingly important healthcare problem with incidence rates having tripled in the last three decades.1 It is now the fifth most common malignancy in the world and the third leading cause of cancer-related mortality worldwide.2 Sorafenib (Nexavar;
Significant experience and organization of liver cancer programs have increased the applicability of sorafenib across patient populations with varying degrees of hepatic function and stages of disease. Sorafenib inhibits the serine-threonine kinases Raf-1 and B Raf and the receptor tyrosine kinase activity of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3 and platelet-derived growth factor b.4 Sorafenib blocks the MEK 1/ERK pathway and can block tumor cell growth.5 It targets angiogenesis by blocking VEGFRs and platelet-derived growth factor.
Recurrence of HCC after liver transplantation (LTx) remains as of today a big detriment in survival. Although there are two potential drug classes that could impact the incidence of recurrent HCC post-LTx, there is currently no consensus on the most reliable treatment approach. Mammalian target of rapamycin inhibitors (mTORs) are immunosuppressants shown to have antitumor activity.6, 7 Another approach is with sorafenib, the multikinase inhibitor approved for unresectable HCC. As we gain more experience with sorafenib, potential applications of its use in liver transplantation in 2014 include: 1) before LTx in patients at high risk of recurrence (those with multiple tumors, high protein-induced by vitamin K antagonist (PIVKA) and alpha-fetoprotein (AFP) levels, prolonged waiting times, elevated AFP after failed locoregional therapy, and microvascular invasion8; 2) as adjuvant treatment post-LTx in high-risk explants, including those with the mentioned characteristics; and 3) for recurrent HCC.
Approximately four years ago, we noticed that patients with recurrent HCC treated with sorafenib were surviving longer. We aim to describe the outcome of patients who received sorafenib after the onset of recurrence for LTx for HCC. We hypothesize that sorafenib has improved survival of these patients. Because transplant recurrences for HCC are infrequent, even in large transplant programs, we realize that this is a pilot study that needs corroboration with a multicenter trial.
Methods
A retrospective review of 247 LTx for HCC (25.9% of all LTx) from
Results
Overall, 22 of 247 HCC LTx (8.91%) recurred in the Model End Stage Liver Disease (MELD) era. Excluding LTx with incidental tumors (n 4 47), 21 patients recurred in the MELD era (11%). Only one incidental tumor recurred (2%). Tumor characteristics by BCLC staging are depicted in Table 2. Eight patients (31%) exceeded the radiologic stage and 12 (46%) were transplanted for Stage B (above
Of 22 post-LTx recurrent patients, nine were treated with sorafenib and begun at escalating doses in all patients adjusted as needed for side effects. Four patients (17%) could not be treated postrecurrence as a result of advanced disease. Nine patients were treated with sorafenib after recurrence in addition to multimodality therapy. By Kaplan-Meier, overall survival was 27 months (SD, 3.2 months) and median survival was 28.4 months. The mean time to recurrence was 16.9 months (SD, 2.8 months), whereas the median was 12 months. The mean survival for sorafenib-treated patients was 36 months (SD, 5.2 months) and the median survival was 42 months compared with a mean of 20 months (SD, 3.3 months) and median of 16.2 months in those not treated with sorafenib (-2 log likelihood ratio, P 4 0.0582) (Fig. 1). By Cox proportional hazards, after adjusting for pathologic and radiologic stage, waiting time, AFP, and total tumor burden, only sorafenib (P 4 0.0233; hazard ratio, 8.528) and pathologic stage had a significant impact on survival. The last five patients with recurrent HCC are alive. Their mean and median posttransplant survival and follow-up is 935 and 961 days, respectively. Their mean and median time to recurrence was 571 and 577 days, respectively. All these five patients are doing fairly well on multimodality therapy, which has included resection, transarterial chemoembolization (TACE), radiation, and sorafenib. Two patients currently refuse to continue sorafenib.
Twenty (91%) of patients with recurrent HCC were treated, whereas two patients, as a result of advanced disease at presentation, were not. Ten patients were treated with sorafenib, 10 with systemic chemotherapy (presorafenib), three received TACE, six received radiation, five underwent resection, and 11 patients had multiple treatments. Sorafenib was dosed at average of 420 mg/day for a mean duration of 10.2 months. Side effects included: hand-foot syndrome, one of 10; rash, two of 10; skin flushing, one of 10; gastrointestinal, one of nine; and seizure, one of nine. Two (22.2%) patients did not tolerate the intended dose.
Discussion
This is a pilot study that demonstrates that patients with recurrent HCC could have improved survival within a very organized and experienced liver cancer and transplant program. With rare exceptions (insurance), treatments were done exclusively at our center. The drug dosage was carefully escalated for tolerability. Immunosuppression and hepatitis C reinfection in the allograftwere carefully monitored. Because HCC recurrence in LTx is one of the critical barriers in improving LTx outcomes, we felt that it was imperative to publish these preliminary data.
This retrospective review of 200 patients transplanted for HCC during the MELD era revealed a recurrence rate of 11 per cent. Thirty-one per cent of these recurrences occurred in patients who exceeded the radiologic stage of the tumors. Sixty-eight per cent exceeded the
The use of sorafenib in recurrent HCC is restricted to small case series and case reports recently reported in the literature.9-13 Vitale et al.,9 in their series of 10 patients who received sorafenib after HCC recurrence after orthotopic liver transplantation (OLT), demonstrated a median survival of 18 months with reasonable tolerance of the drug by patients. Sotiropoulos et al.,10 in their series of 14 patients, showed a median survival of 25 months. The study by Teng had only five patients receiving adjuvant treatment and six patients receiving palliative treatment. Patients in the adjuvant and palliative groups exhibited better overall survival than those in the control groups.14 The Gomez study was an uncontrolled study of 31 patients with HCC recurrence who received mTORs and sorafenib. The median survival was 19 months. It concluded that mTORs and sorafenib could be used concomitantly despite notable toxicity.15 Yan et al., based on results of their rat model of OLT for HCC, suggested that sorafenib significantly inhibited ERK phosphorylation, resulting in lower tumor proliferation rate and angiogenesis in the posttransplant recurrent tumor tissues and higher tumor apoptosis rate. They believe that these molecular mechanisms result in improved progression-free survival and the overall survival in their animal model.16
Our study is not unique. This is a pilot study of 10 patients who were treated with a variety of multimodality therapies for HCC recurrence post-LTx and had the opportunity to receive sorafenib. They were compared with historic controls, which had no access to the drug. We have few patients and cannot ascribe the outcome to a single factor, including sorafenib. Nevertheless, the last five patients treated with sorafenib in this study remain alive and have a median follow-up of 32 months.
There are several factors that could explain the recent improved results in recurrent HCC and transplants for HCC in general. The latter we presented in 2013 at the annual meeting of the
Sorafenib is now used widely in our liver transplant and cancer program. We began with participation in a dose escalation trial in unresectable HCC (
One more clinical aspect worth mentioning is the effect of obesity on recurrent HCC. Data fromour group and from
Conclusions
The recurrence rate of HCC after LTx excluding incidental tumors was 11 per cent and remains acceptable, particularly with recent outcomes. A large proportion of recurrent HCC occurs in understaged tumors. Sorafenib and multiple upgrades in a liver cancer program have improved survival. Until we decrease recurrences further and prove through multicenter trials that sorafenib can prevent recurrences or prolong survival after recurrence, LTx outcomes for HCC will not improve. One exception to this would be eradication of hepatitis C virus post-LTx, which could begin this year with the use of direct antiviral agents. The wider applicability of LTx for HCC, downstaging, and other factors has resulted in a large proportion of patients above the
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Presented at the Annual Scientific Meeting and Postgraduate Course Program,
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