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      News & Perspective Drugs & Diseases CME & Education Academy Video Decision Point
      Drugs & Diseases > Oncology

      Fibrolamellar Carcinoma Treatment & Management

      Updated: Oct 17, 2022
      • Author: Michael A Choti, MD, MBA, FACS; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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      Treatment

      Approach Considerations

      Surgical resection or transplantation is the standard of care for fibrolamellar carcinoma (FLC) for eligible patients. [82] Trans-arterial chemo-embolization (TACE) may be a useful option in patients who have unresectable disease. [83, 84] TACE has also been used as neoadjuvant therapy, to facilitate subsequent tumor resection. [85]

      The role of neoadjuvant or adjuvant chemotherapy is controversial. FLC is not typically responsive to chemotherapy. In some cases, chemotherapy had no effect on survival or recurrence in patients who received chemotherapy after surgery. In contrast, other studies have found that patients who received chemotherapy in neoadjuvant and adjuvant settings fared better than those with surgery only. [76]  

      While not well studied, radiation therapy has been used to treat recurrent FLC in isolated case reports. Peacock et al demonstrated an 85.9% decrease in tumor volume of FLC metastases using 40 Gy in 10 fractions over a 13-day period. [86]

      In addition to systemic chemotherapy, research has also focused on taking advantage of the new understanding of the pathogenesis and molecular genetics of FLC. For example, anecdotal reports of FLC response to rapamycin analogs have been substantiated by laboratory evidence of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) activation in these tumors. [87, 88] However, a phase II multi-institutional, three-arm trial of estrogen deprivation therapy, alone or in combination with the mTOR inhibitor everolimus, did not demonstrate clinical activity in advanced FLC. [89]

      In another study using SEER data, which included 225 patients with fibrolamellar carcinoma, survival decreased with increasing age. Median survival was 85 months in patients age ≤ 19 years, 29 months in those age 20-59 years, and 12 months in those age ≥60 years. Although patients age ≤ 19 years had more advanced disease, with positive lymph nodes, they were more likely to receive surgical interventions (eg, wedge or segmental resection, lobectomy or extended lobrectomy, liver transplantation. [26]

      Next:

      Medical Care

      Chemotherapy for metastatic fibrolamellar carcinoma (FLC) is as for metastatic typical hepatocellular carcinoma (HCC). Single-agent chemotherapy or combinations of chemotherapeutic drugs give responses of no more than 25%, with questionable benefit for overall survival.

      Sorafenib is an orally delivered small molecule that inhibits several different protein kinases, including Raf-1 and B-Raf, platelet-derived growth factor β (PDGFR-β), and vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. Sorafenib targets both tumor growth (Raf-MEK-ERK pathway) and neoangiogenesis (VEGFRs, PDGFR-β), both of which are thought to be important in the pathogenesis of typical HCC.

      A randomized controlled trial of sorafenib in 602 patients with advanced typical HCC and well-compensated cirrhosis demonstrated a survival benefit with sorafenib as compared with placebo, corresponding to a 3-month increase in median survival (10.7 versus 7.9 mo). [90]  A similar study will likely never be performed in FLC due to the rarity of the disease. It is unclear whether the data on sorafenib for typical HCC are generalizable to FLC. There are not yet any reports in the literature describing sorafenib use in FLC.

      A phase II clinical trial reported in 2003 evaluated 21-day courses of systemic continuous 5-fluorouracil repeated monthly and thrice-weekly subcutaneous recombinant interferon α-2b in a mixed population of 43 patients with FLC or typical HCC. [91] All of these patients were ineligible for surgical therapy due to extent of hepatic disease as determined by CT scan, but none had extrahepatic disease. Of nine patients with FLC, eight were radiologically assessed for response, which showed one complete response (CR), four partial responses (PR), and one minor response (MR). The median survival of the FLC patients was 23 months, compared with 15.5 months for typical HCC (statistical significance not reported).

      Of note, a major reason the authors chose this treatment regimen was that they anticipated it would be well tolerated by patients with cirrhosis. Although the regimen was in fact well tolerated in this trial, none of the FLC patients had cirrhosis. Because FLC patients generally do not have cirrhosis, chemotherapeutic regimens that might not be appropriate for typical HCC might be of use in FLC.

      In a study of immunochemotherapy with 5-fluorouracil, interferon, and nivolumab in adolescent and young adult patients (22 treated, 14 evaluable) with unresectable, metastatic, refractory, or relapsed FLC, median progression-free survival was 9 months. After 26 months, over 90% of patients were still alive; 5 patients had achieved clinical remission, 8 patients were stable or improving, and 1 patient had experienced progression. [92]

       

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      Next:

      Surgical Care

      Optimal management for most hepatic malignancies, including typical hepatocellular carcinoma and fibrolamellar carcinoma, is complete surgical resection (eg, wedge resection, anatomic liver resection, or total hepatectomy with orthotopic liver transplantation). There may be occasional utility in treating fibrolamellar carcinoma with neoadjuvant chemotherapy or trans-arterial chemo-embolization (TACE) with the goal of downstaging the tumor to allow resection. [83]

      Hepatic resection

      Cirrhosis often limits the feasibility of liver resection in patients with typical hepatocellular carcinoma (HCC) because cirrhotic patients have increased perioperative risk and require a larger future liver remnant to be left behind to allow adequate liver function. In contrast, fibrolamellar carcinoma (FLC) is rarely associated with cirrhosis, and patients are often young and otherwise healthy. For this reason, aggressive liver resections can be more readily undertaken in patients with FLC than in those with typical HCC.

      Several factors are associated with a better prognosis following surgery, including younger age at diagnosis, earlier tumor stage at diagnosis, and absence of large vessel invasion or thrombosis. [20] ​ The ability to perform complete resection has been reported to be one of the most important and well-described prognostic factors for FLC. [20, 46, 24] Factors associated with a particularly poor prognosis include lymph node metastasis, multiple tumors, metastatic disease at presentation, and vascular invasion. [20, 77]

      Patients with resected FLC generally have a prognosis similar to that for noncirrhotic patients with resected typical HCC. [9, 25] Aggressive surgical approaches, even for recurrent disease, can be undertaken with good results. [29]

      Orthotopic liver transplantation

      Total hepatectomy followed by orthotopic liver transplantation (OLT) should be considered in patients with unresectable FLC that is confined to the liver.  An analysis of 63 patients who received liver transplanation for FLC between October 1988 and January 2013 had an overall survival at 1, 3, and 5 years of 96%, 80%, and 48%, respectively, while comparable rates in HCC patients were 89%, 77%, and 68%. Six patients had tumor recurrence (10%). Model for End-stage Liver Disease (MELD) score and cold ischemic time were the strongest predictors of overall survival in FLC patients. [93]  

      Even among patients who develop tumor recurrence, the time to recurrence is significantly longer in patients with FLC than in those with typical HCC. [94] This may be a result of more indolent behavior by FLC versus typical HCC. Alternatively, it may result from the fact that accompanying cirrhosis in typical HCC increases the risk of recurrence (including development of a second primary tumor) via a field effect.

      Orthotopic liver transplantation can result in long-term survival but is a resource-intensive treatment approach. In typical HCC, orthotopic liver transplantation confers the advantage of removing the at-risk cirrhotic liver in addition to the tumor itself. In FLC, this theoretical advantage is likely not present because no such field effect is present (due to the lack of cirrhosis in most cases).

      As such, it is not clear that the use of donor organs in patients with FLC is an appropriate use of this scarce resource. [90] Newer innovative approaches (eg, adult living-related donations, split-liver techniques, and potential use of marginal donor organs) may allow for a future increase in the use of orthotopic liver transplantation for FLC.

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