Open Access

Complete cure of a patient with HBV‑associated hepatocellular carcinoma with lung metastasis using interferon and survival up to 108 months: A case report and literature review

  • Authors:
    • Fang Wang
    • Hongmin Lv
    • Yan Li
    • Tao Han
    • Hui Liu
    • Kefeng Jia
    • Fang Liu
    • Yanying Gao
    • Fengmei Wang
  • View Affiliations

  • Published online on: June 28, 2018     https://doi.org/10.3892/ol.2018.9033
  • Pages: 2979-2988
  • Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Hepatocellular carcinoma (HCC) has a poor prognosis due to its asymptomatic onset and susceptibility to metastasis. The survival of patients with advanced HCC is 6‑12 months. As a first‑line medicine for the control of hepatitis B virus, interferon (IFN) is also capable of inhibiting tumor growth and modulating immunity. However, treatment of HCC with lung metastasis using IFN has been rarely reported. The present study reports the case of one patient with HCC having lung metastasis who underwent a one‑time treatment with transcatheter arterial chemoembolization (TACE) and was subsequently completely cured by single peginterferon α 2a (PEG‑IFNα2a); and has survived up to 108 months. A 53‑year‑old male patient diagnosed with HBV‑related HCC with lung metastasis underwent TACE using floxuridine (FUDR) 500 mg, cisdiamine dichloroplatinum (CDDP) 20 mg, mitomycin 10 mg, and ultrafluid lipiodol 10 ml, together with local thoracic aorta chemotherapy using FUDR 250 mg and CDDP 20 mg. His metastatic lung cancer aggravated. However, after 9 months of treatment with subcutaneous injections of PEG‑IFNα 2a once per week, the metastatic lung foci gradually shrunk until disappearance and the HCC lesion stabilized without progression. According to the World Health Organization criteria for the efficacy of solid tumors, this was a case of complete response. Upon follow‑up up to 108 months his metastatic lung cancer had disappeared and HCC did not recur. Therefore, IFN intervention may be an appropriate novel adjuvant therapy for patients with HCC with lung metastasis and requires further attention and study.

Introduction

Hepatocellular carcinoma (HCC) is the second cause of male cancer-related mortality worldwide. In 2012, 782,500 new patients with HCC and 745,500 cases of death due to HCC were reported, of which 50% were reported in China (1). HCC with extrahepatic metastasis seriously impacts survival, and metastatic lung cancer is the most common extrahepatic metastasis, comprising around 53.8% of all extrahepatic metastasis (2).

No effective therapy is currently available for lung metastatic HCC. According to reports, pneumonectomy is the most effective therapeutic modality. However, prior studies revealed that only 2.6% of patients with HCC with lung metastasis met the operative indication, and surgery benefited only those who had less than four lung metastatic foci with diameters less than 3 cm (3). In China, HCC is mostly secondary to hepatitis B virus-related liver cirrhosis, with multiple lung metastatic foci and poor clinical operability (4). Chemotherapy exhibits certain efficacy for lung metastatic HCC. However, the majority of chemotherapy drugs metabolize in the liver. Hepatotoxicity and bone marrow suppression are the major limitations of chemotherapy. Besides, a universally recognized chemotherapy regimen is still lacking. Molecular targeted therapy of sorafenib is effective for advanced HCC; however, HCC with lung metastasis responds to it poorly (5). Researchers have also explored other therapeutic modalities, such as local radiotherapy, radiofrequency ablation, and so on, but no assertive efficacy has been achieved. Overall, no standardized and effective therapeutic strategy exists for lung metastatic HCC till date.

A recent investigation indicated that interferon (IFN) prolonged survival in patients with HCC who underwent radical resection, and the combination of IFN with cytokine-induced killer adoptive cellular therapy prevented recurrence (6). Complete cure of lung metastatic HCC using single IFN has not been reported till date.

The present study reported one case of HCC with multiple lung metastatic lesions. After one time of transcatheter arterial chemoembolization (TACE) and local chemotherapy via thoracic aorta, lung metastatic foci evidently increased. Despite that, 4 months of continuous treatment with peginterferon α 2a (PEG-IFN α 2a) led to a gradual reduction in alpha-fetoprotein (AFP) from >1,000 ng/ml to normal prior to treatment and resulted in the gradual disappearance of metastatic lung cancer and stability of HCC lesions without recurrence. Till the date of writing this report, the patient lived a high-quality life for 108 months, reaching a clinical cure according to the World Health Organization (WHO) prognostic criteria.

Case report

A 53-year-old male patient, living in Tianjing, China, had a medical history of diabetes, hepatitis B e antigen-negative chronic hepatitis B, and a family history of hepatitis B and liver cancer (with the death of his mother and one brother from HBV-related HCC), and without a history of blood transfusion. In 2007, the patient started lamivudine, 100 mg qd, for controlling HBV with HBV DNA 5.3×106 cs/ml and alanine aminotransferase 102 U/l. In April 2008, radioimmunoassay estimated a concentration of >1,000 ng/ml of AFP in the patient. Moreover, color ultrasonography revealed a hypoechoic solid mass of size 4.0×4.0 cm2 in the right anterior lobe of the liver with uneven density and irregular edge, which was considered as HCC. It also showed enlargement of the caudate lobe of the liver, widening of the hepatic fissure, and widening of the portal vein with a diameter of 1.1 cm, in addition to splenomegaly, which was considered as liver cirrhosis. Furthermore, enhanced computed tomography (CT) of the upper abdomen revealed a soft tissue mass with a diameter of 2.26×4.16 cm2 in the right anterior lobe of the liver, presenting a low-density soft tissue in the plain scanning, mild enhancement of the density in the arterial phase, and yet nonhomogeneous enhancement of the density in the portal phase, along with an evident reduction in the mass density in the equilibrium phase, which was considered as HCC (Fig. 1A). Moreover, chest CT exhibited multiple small nodules in the right inferior lobe of the lung, with a maximum diameter of 0.5 cm, which were considered as metastatic cancer (Fig. 1B). Also, in April 2008, the digital subtraction angiography displayed enlarged and tortuous anterior and posterior branches of the right hepatic artery and the image of a tumor with a diameter 4.1×4.0 cm2 in the right anterior lobe of the liver in the parenchymal phase, along with five small nodules of <0.5 cm in the right inferior lobe of the lung. In summary, the ultrasound displayed an intrahepatic nodule more than 2 cm in size. The typical dynamic change in the nodule was detected using a dynamic imaging method, presenting vessel density enhancement of the hepatic mass in the arterial phase and rapid elution in the delayed phase under enhanced CT. The AFP level was measured to be >200 ng/ml. According to the ‘Clinical Guidelines for Hepatocellular Carcinoma’ issued in the year 2005 by the American Association for the Study of Liver Diseases (AASLD), HCC was the definitive diagnosis without the need of biopsy. Gastroscopy indicated mild esophageal varices. Therefore, the preliminary diagnosis was primary HCC, metastatic lung cancer, compensated HBV-related cirrhosis, and chronic hepatitis B. On the request of the patient and his kin as well as signed informed consent, TACE (Fig. 1C) was performed. Specifically, floxuridine (FUDR) 500 mg and cisdiamine dichloroplatinum (CDDP) 20 mg were infused through the proper hepatic artery for chemotherapy, and superselective embolization of the right hepatic artery was conducted using 10 mg mitomycin plus 10 ml of ultrafluid lipiodol. Moreover, 250 mg FUDR and 20 mg CDDP were infused through the bronchial artery of the thoracic aorta at the bifurcation of trachea level for chemotherapy of lung metastatic foci. The patient had HCC with metastatic lung cancer, in phase IV of the TNM staging, at initial presentation. According to the WHO criteria for solid tumor response, TACE for local chemoembolization is a partial remission strategy for treating HCC with lung metastatic foci and the patient survival is expected to be less than 6 months.

Figure 1.

Enhanced CT scanning of the upper abdomen and chest CT scanning prior to treatment and TACE imaging. (A) In April 2008, a soft tissue mass 2.26×4.16 cm2 in size, with a low density was displayed in the right anterior lobe of the liver. This was observed in the plain scanning, mild enhancement of density in the arterial phase and the nonhomogeneous enhancement of the density in the portal phase, as well as with an evident reduction in the mass density in the equilibrium phase. (B) Chest CT exhibited multiple small nodules in the right inferior lobe of the lung with a maximum diameter of 0.5 cm, which were considered as metastatic cancer. (C) In April 2008, the digital subtraction angiography displayed enlarged and tortuous anterior and posterior branches of the right hepatic artery, and the image of a tumor with 4.1×4.0 cm2 in size in the right anterior lobe of the liver in the parenchymal phase, along with five small nodules of <0.5 cm in the right inferior lobe of the lung, which was considered as HCC with metastatic lung cancer. Under the request of the patient and his kin TACE was performed. A total of 500 mg FUDR and 20 mg CDDP were infused through the proper hepatic artery for chemotherapy and superselective embolization of the right hepatic artery was conducted using 20 mg mitomycin 20 mg plus 10 ml ultrafluid lipiodol. In addition, 250 mg FUDR and 20 mg CDDP were infused through the bronchial artery of the thoracic aorta at the bifurcation of trachea level for chemotherapy of lung metastatic foci. After TACE, good lipiodol sedimentation was observed in the lesion in the right anterior lobe of the liver. CT, computed tomography; TACE, transcatheter arterial chemoembolization; HCC, hepatocellular carcinoma; FUDR, floxuridine; CDDP, cisdiamine dichloroplatinum.

In June 2008, following 2 months of TACE, a review check of the patient showed white blood count of 3.00×109/l, platelet count of 71×109/l, and AFP of >400 ng/ml. Also, enhanced CT scanning of the upper abdomen revealed post-TACE change of the soft tissue mass in the right anterior lobe of the liver, good lipiodol sedimentation, and relative stability of the HCC lesion. Chest CT scanning displayed multiple diffuse nodules in the bilateral lung, with the increased number and enlarged volume. Hence, metastatic cancer was considered progressive. The patient refused to take targeted therapy of sorafenib. In systemic consideration of compensated cirrhosis, Child-Pugh A grade, and normal blood routine, in addition to mild esophageal varices by gastroscopy, PEG-IFNα 2a (180 µg qw) was elicited under the informed consent of the patient and his kin. During treatment, regular monitoring of the patient was done, including blood routine, AFP, liver function, and IFN-associated adverse effects, in addition to liver- and lung-imaging changes. The AFP levels gradually reduced with IFN use. In August 2008, 2 months after the IFN intervention, the AFP level was >400 ng/ml, which decreased to 5.8 ng/ml after 4 months, in October 2008. Since then, the AFP level of the patient stayed within the normal range. The patient once had transient leukopenia and neutropenia, but the leukocyte and neutrophil levels resumed to normal in 3 days after temporary subcutaneous administration of the recombinant human granulocyte colony-stimulating factor (rhGCSF) injection, 75 µg per day. IFN was continued, and no other IFN-associated adverse effects were recorded.

In March 2009, 9 months after the IFN intervention, a full hospital review check of the patient showed an AFP of 6.27 ng/ml. An enhanced CT scanning of the upper abdomen revealed the post-TACE change of HCC in the right anterior lobe of the liver. Additionally, chest CT scanning revealed multiple nodules in the bilateral lung, which was considered as metastatic cancer, but with marked improvement than before. Both HCC and metastatic lung cancer met the standard for a complete remission according to the WHO criteria for solid tumor response. In the following 8 years, IFN therapy was continued, and the regular review check displayed stable cancer nodules by enhanced CT scanning of the upper abdomen and chest CT scanning (Fig. 2). In December 2009, HBV mutation was detected in the patient, of which the 204th residue methionine (M) in the YMDD motif of polymerase C was replaced by isoleucine (I), with HBV DNA of 2.7×104 cs/ml. The situation improved after adding adefovir dipivoxil combined with lamivudine to control the virus. In February 2014, the patient terminated antiviral drugs on his own accord. After 2 months, on April 23, 2014, the review check showed HBV DNA of 9.65×108 cs/ml, and the YMDD motif of the polymerase C was resumed to wild type. Antiviral therapy with entecavir was given till date, and HBV DNA was detected to be negative (Fig. 3). Also, the AFP levels were monitored to be normal. No other HCC-related therapy was enforced ever since (Fig. 4). In April 2017, the review check showed AFP of 1.32 ng/ml, hepatitis B surface antigen (HBsAg) of 45.43 IU/ml, and negative HBV DNA. An enhanced CT scanning of the upper abdomen displayed a stable HCC nodule, and the chest CT revealed micronodules in the bilateral lung. According to the WHO criteria for solid tumor response, the patient reached a complete remission and survival of up to 9 years, with a good quality of life (QOL) reflected by the Karnofsky Performance Scale score of 100, performance status grade 0, and QOL score of 60. Currently, the patient sticks to the average follow-up, once every 3–4 months, and his general condition, cancer status, and potential adverse effects are being monitored (Tables I and II). Continuous attention is being paid to the disease status of the patient.

Table I.

Monitoring of interferon therapy-related adverse effects during treatment.

Table I.

Monitoring of interferon therapy-related adverse effects during treatment.

Follow up date (month/year)WBC (3.5–9.5)×109/lPLT (100–300)×109/lIRTCa (2.03–2.54) mmol/lP (0.90–1.34) mmol/lTSH (0.27–4.2) mIU/lCD4 (32.8–52.8)%CD8 (19.7–38.9)%Gastroscopy
04/20083.367All negativeEV, Li, F1, RC(−)
06/200837142.841.1
04/20093.0183All negative2.390.6628.725.4
05/20103.819336.331.3
12/20103.5786EV, Lmi, F2, RC(−)
07/20114.1310728.429.1
03/20123.71140
12/20124.96112EV, Lmi, F2, RC(−)
04/20135.25119All negative2.220.635.133.1
08/20144.771042.191.030.21
12/20143.871012.080.64Esophagitis, superficial
gastrotis
06/20154.0688All negative2.080.81
10/20163.5497All negative0.75
04/20173.6389All negative2.190.76

[i] WBC, white blood cells; PLT, platelets; IRT, immunologic-related test; Ca, serum calcium; P, serum phosphorus; TSH, thyroid-stimulating hormone; CD, cluster of differentiation; EV, esophageal varices; IRT included antinuclear antibody, anti-mitochondrial antibody, anti-mitochondrial antibody M2 subtype, SP100 antibody, anti-glucoprotein 210 antibody, anti-SSA antibody, anti-SSB antibody, anti-dsDNA antibody, anti-smooth muscle actin antibody, anti-liver kindey microsome antibody, anti-soluble liver antigen antibody, anti-Sm antibody, IgE, IgG, IgA and IgM.

Table II.

Clinical follow-up records of potential adverse effects during IFN therapy.

Table II.

Clinical follow-up records of potential adverse effects during IFN therapy.

IFN-associated adverse effectsFollow-up and management
Influenza-like symptomsFever (T>37.3°C)Transient, disappeared after 1 week
HeadacheTransient, disappeared after 1 week
Muscle and joint soreTransient, disappeared after 1 week
Whole-body discomfortTransient, disappeared after 1 week
Gastrointestinal reactionsNausea, vomiting, inappetenceNo occurrence
Changes in the skin and hairHair lossEvident in the first year and stable in the following years
Whole-body itching, rashNo occurrence
Symptoms of bone marrow suppressionLeucopeniaTransient, no interference with use after symptomatic management
ThrombocytopeniaTransient, no interference with use after symptomatic management
Symptoms of the nervous systemFatigue, insomnia, indifference, lack of initiative, depressed to suicideNo occurrence
Thyroid dysfunction symptomsChange in T3, T4, and TSHNo occurrence
Thyroid autoimmune antibodyNo occurrence
Autoimmunity diseasesDiabetesStable blood glucose level
Thyroiditis, autoimmune hepatitis, biliary cirrhosisNo occurrence
Ocular abnormalitiesInfraorbital hemorrhageNo occurrence
Retinal hemorrhageNo occurrence
Hearing impairmentTinnitus, hearing lossNo occurrence
Cardiovascular systemArrhythmia, pericarditisNo occurrence
Respiratory systemInterstitial pneumonia, pulmonary embolismNo occurrence

[i] IFN, Interferon; TSH, thyroid-stimulating hormone.

Discussion

HCC metastasis and recurrence severely impact patient survival and QOL. However, no standardized effective therapy strategy is available for lung metastatic HCC till date. Personalized therapy deserves further exploration. Radical surgery is recognized as the cure, but the number of patients who met the operative indication is limited. Systemic chemotherapy is also one of the common therapy strategies, but it is not extensively appreciated because it deteriorates cancer recurrence and showed no effect on survival improvement in postoperative patients with HCC and cirrhosis (7). Molecular targeted therapy of sorafenib is effective for advanced HCC; however, HCC with lung metastasis responds to it poorly (5). Additionally, the existence of multidrug resistance gene leads to poor chemotherapeutic efficacy and accelerated adverse effects, imposing risks on patient's safety.

In previous studies, the prognosis of HCC with lung metastasis was poor, but administering IFN was beneficial (Table III) (815). A recent report documented a successful cure of lung metastatic HCC by chemotherapy, in which Japanese researchers applied S-1 (the oral fluoropyrimidine), a complex of tegafur, gimeracil, and oteracil potassium, combined with IFNα to treat 11 patients who lived for more than 1 year. One of them lived for more than 5 years with the disappearance of multiple metastatic lesions (16). From the overall perspective, no standardized effective strategy still exists for systemic chemotherapy, and adequate evidence-based analysis is lacking. The patient in the present case study lived up to 108 months without cancer, taking no subsequent chemotherapy after TACE, except IFN. This was not reported before and deserved further exploration.

Table III.

Previous reports of cases with interferon treatment for hepatocellular carcinoma with lung metastasis.

Table III.

Previous reports of cases with interferon treatment for hepatocellular carcinoma with lung metastasis.

Author, refAge/sexHistoryLocation of HCCTreatment for HCCRecurrence timeRecurrence siteTreatment for recurrenceType of interferonOther therapyPrognosis
Katsura et al (8)77/maleNALeft lobeTACE and left hepatic lobectomy7 monthsMultiple bilateral lungsS-1IFNNoAlive with the disease details were not shown, alive with good condition without recurrence and progression of tumors
Oh et al (9)49/maleCHB, cirrhosis, RFA for a single HCC (4 cm, segment 7)Intrahepatic recurrence of HCC with extensive lung metastasesHAIC comprising epirubicin and cisplatin, and systemic infusion of 5-FU13 monthsA single small HCC lesion in the left lobeHAIC, percutaneous intratumoral chemoinjection therapy with 5-FU and IFN-γIFN-γNoDisease-free intervals for the liver and lung were 41 and 54 months, respectively
Kilickap et al 10)37/maleCHB, HCCRight lobe, 49×61 mmRight hepatic lobectomy1 monthThoracic 6–8 vertebraeT6-8 laminectomy,IFN-αNoAlive without disease on lamivudine and IFN-α, disease-free for 3 years; followed up about 10 years after diagnosis
3 yearsThe left lower lobelocal radiotherapyIFN-αLamuvidine
3 monthsof the lung, 1 cmResected lung metastasis
4 years finding but stable, progression on 5 years 6 monthsThe left kidney, from 13×13 mm increasing to 25 mmPartial nephrectomyPegylated IFN-αLamuvidine
Tanaka et al (11)60/maleHepatitis CSegment 3, 44 mm in diameterPartial hepatectomy9 months after the surgeryIntra abdominal solitary lymph node metastasisRemoval of the lymph nodeNA Alive with no recurrence 19 months, 30 months after the initial operation
Nakamura et al (12)54/malePVT and multiple intrahepatic metastasesThe bilateral lobes of the liverExtended left lobectomy, intra-arterial 5-FU infusion chemotherapy, IFN-α to treat the lesions in the residual liver7 monthsRecurrent tumors in the spleen and residual liverS-1IFN-α Alive with no recurrence 32 months after initial hepatic resection
Recurrent tumors in the lungS-1, resectedIFN-α
Nakamura et al (13)56/malePVT and multiple intrahepatic metastasesExtended left lobectomy and a partial resection of the liverExtended left lobectomy and a partial resection of the liver, after two weeks, intra arterial 5-FU infusion, IFN-α4 monthsHepatic vein tumor thrombus, inferior caval veinTS-1IFN-α NA
8 monthsMutiplle pulmonary metastases
Nakamura et al (14)52/maleNARight lobeRight lobectomy5 monthsMultiple recurrences in the live and lungTAE, UFT and IFN-αIFN-α and IFN-β IFN-α, TS-1/ IFN-β5-FU/ CDDP/Survived 31 months with no disturbance in quality of life
Kanda et al (15)64/maleHCC with lung metastasisNAγ-interfeorn and mitoxantroneNANANAIFN-γHCFU 400 mg/ body everyday for 8 monthsStill alive

[i] TACE, transcatheter chemoembolization; TAE, transcatheter embolization; RFA, radiofrenquency ablation; HAIC, hepatic arterial infusion chemotherapy; CHB, chronic hepatitis B; HCC, hepatocellular carcinoma; PVT, portal vein thrombus; NA, not available; IFN, interferon; 5-FU, 5-fluorouracil; TS-1, Gimeracil and Oteracil Porassium Capsules; UFT, Tegarur-uracil, Ftoyafuy; CDDP, cisdiamine dichloroplatinum.

IFN is a multifunctional cytokine with antiviral and antitumor activities, which is probably more beneficial for HBV-related patients with HCC. After surgical resection of HCC, IFN is the most effective adjuvant therapeutic modality for survival improvement compared with other common adjuvant therapeutic strategies for HCC (6). A variety of meta-analyses indicated that IFN improved the nonrecurrence survival and overall survival following surgical resection of virus-related HCC (1719). Moreover, IFN intervention remarkably attenuated mortality and recurrence in HBV-related patients with HCC having a therapeutic history of TACE (20). In the patient in the present case study, TACE was used comprising CDDP and FUDR for HCC, and CDDP/FUDR achieved a good tumor response (21). Because of the local and one-time therapy using CDDP/FUDR, IFN intervention was speculated to be the key to the successful cure of patients based on several potential reasons as follows.

First, IFN imparts direct and indirect antitumor effects. From one aspect, IFN acts directly on tumor cells, inhibiting cell proliferation and promoting apoptosis possibly via the mechanisms as follows: i) it is mainly involved in biological behaviors, such as proliferation, differentiation, and apoptosis, via a Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway (22); ii) it promotes apoptosis of the HCC cells via transactivation of P38/mitogen-activated protein kinase pathway (23); iii) it activates p63 in the S/G2/M phases of the cell cycle and causes cells to remain quiescent in phase G1, thus inducing apoptosis of the HCC cells (24) and iv) it induces autophagy via JAK/STAT and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways and is crucial in the inhibition of cell proliferation (25). From another aspect, IFN exerts an indirect antitumor effect by activating host antitumor immune response via mechanisms as follows: i) it transactivates PI3K/Akt signaling pathway and thus activates natural killer (NK) cells to execute antitumor activity (26); ii) it enhances NK cell-mediated antitumor immunity via activation of host dendritic cells (27); iii) it promotes tumor-specific CD8+ T cells, thus increasing the response of cytotoxic T lymphocytes to enhance antitumor activity (28) and iv) it inhibits proliferation of regulatory T cells (Treg) and attenuates Treg-mediated immune suppression to play an indirect antitumor role (29).

Second, IFN inhibits metastatic lung foci. IFN intervention could not only continuously inhibit HCC growth but also block the proliferation of the metastatic foci in the lung. The epithelium mesenchymal transition (EMT) is closely associated with tumor metastasis, and matrix metallopeptidase 9 (MMP-9)-mediated EMT is essential in the process, while downregulation of MMP-9 can hinder HCC metastasis (30). Macrophage in the lung secretes MMP-9 to promote the proliferation and migration of metastatic lung foci, and IFN intervention decreases MMP-9 levels to control metastatic lung foci (31). IFN also inhibits metastasis and recurrence of HCC via downregulation of VEGF-mediated angiogenesis (32).

Long-term IFN therapy also benefits patients (33). Drug termination in the patient who underwent IFN antitumor therapy elicits upregulation of MMP-9 and macrophages in the lung, explaining the increase in recurrence and lung metastasis after drug termination according to clinical observations (34). Of course, attention should be paid to adverse effects of IFN therapy, for example hematologic disorder and influence on thyroid functions and nervous system. Intolerance to these adverse effects interferes with the extensive and long-term application of IFN in patients with HCC. With an optimistic attitude toward life, the patient in the present study took IFN for a long duration. Close monitoring of the changes in blood routine, blood sugar, thyroid function, and immunity-related tests exhibited negative abnormality. The patient responded and tolerated well to IFN intervention, which was also considered as a critical element for benefits to the patient.

Finally, the antiviral activity of IFN likely benefits patients. The disappearance of HBsAg is the ultimate goal of chronic hepatitis B therapy, which contributes to the control of the incidence rate of HCC. When IFN decreases the HBV DNA levels, it also regulates the immune response leading to limitation of HBsAg, and its combinatory therapy with nucleotide analogues probably imposes a synergistic effect on the maximal reduction in the prevalence rate of HBV-related HCC (35). In the present study, the patient once had the HBsAg level as high as 25,000 IU/ml during the last 8 years or more, which was reduced to 45.43 IU/ml (current) by the combinatory antiviral therapy of IFN with various nucleotide analogues, reflecting good immunological control of HBV infection in the patient system. Although the nucleotide analogue was capable of improving survival in patients with HCC, it could not treat HCC on its own. Therefore, IFN was believed to be indispensable in fighting against HBV and HCC, which was probably the essential cause leading to the complete clinical cure and high QOL for the patient. Until now, this is the only case reported with a survival of 108 months and with regular follow-up. This patient was followed up regarding disease progression and change.

In summary, this study provided a novel idea for treating patients with HCC having lung metastasis, particularly HBV-related HCC. IFN intervention, as the main adjuvant therapy, resulted in complete disappearance of metastatic lung cancer and led to stable HCC without progression, in addition to a complete clinical cure and long-term survival. Prior to treatment, if HBV whole-genome sequencing from the patient or genetic test of the HCC tissue had been performed, or the immune state of the patient had been uncovered, for example, the measurement of IFN receptors, it would have helped to sort out the beneficial factors of IFN cure of HBV-related HCC. Given IFN exerts anti-HBV and antitumor effects, long-term IFN intervention is a promising strategy as a critical adjuvant therapy for HBV-related HCC with lung metastasis, which is worth studying further. Also, the IFN dose and treatment course requires attention, together with its safety and applicable population.

Acknowledgements

Not applicable.

Funding

This study was funded by the Major Projects of the Ministry of Science and Technology of China (grant no. 2017ZX10302202) and the Tianjin Municipal Health and Family Planning Commission (grant nos. 16KG151 and 2014KY03).

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

FW observed the patient's condition, collected clinical data and wrote the manuscript. HML, YL, TH, HL, FL and YG participated in the clinical treatment and follow-up record of the patient over the past 9 years. KJ conducted the TACE treatment and image data follow-up of the patient. FMW decided on the patient diagnosis and treatment as well as the design and revision of the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The present study was approved by the Ethics committee of Tianjin Third Central Hospital in accordance with the ethical standards mentioned in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from the patient included in the study.

Patient consent for publication

Informed consent was obtained from the patient for the publication of their data and associated images.

Competing interests

The authors declare that they have no competing interests.

References

1 

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Natsuizaka M, Omura T, Akaike T, Kuwata Y, Yamazaki K, Sato T, Karino Y, Toyota J, Suga T and Asaka M: Clinical features of hepatocellular carcinoma with extrahepatic metastases. J Gastroenterol Hepatol. 20:1781–1787. 2005. View Article : Google Scholar : PubMed/NCBI

3 

Chen F, Sato K, Fujinaga T, Sonobe M, Shoji T, Sakai H, Miyahara R, Bando T, Okubo K, Hirata T and Date H: Pulmonary resection for metastases from hepatocellular carcinoma. World J Surg. 32:2213–2217. 2008. View Article : Google Scholar : PubMed/NCBI

4 

Hu HH, Liu J, Lin YL, Luo WS, Chu YJ, Chang CL, Jen CL, Lee MH, Lu SN, Wang LY, et al: The rs2296651 (S267F) variant on NTCP (SLC10A1) is inversely associated with chronic hepatitis B and progression to cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B. Gut. 65:1514–1521. 2016. View Article : Google Scholar : PubMed/NCBI

5 

Yau T, Chan P, Ng KK, Chok SH, Cheung TT, Fan ST and Poon RT: Phase 2 open-label study of single-agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B-endemic Asian population: Presence of lung metastasis predicts poor response. Cancer. 115:428–436. 2009. View Article : Google Scholar : PubMed/NCBI

6 

Zhu GQ, Shi KQ, Yu HJ, He SY, Braddock M, Zhou MT, Chen YP and Zheng MH: Optimal adjuvant therapy for resected hepatocellular carcinoma: A systematic review with network meta-analysis. Oncotarget. 6:18151–18161. 2015. View Article : Google Scholar : PubMed/NCBI

7 

Ono T, Yamanoi A, El Assal Nazmy O, Kohno H and Nagasue N: Adjuvant chemotherapy after resection of hepatocellular carcinoma causes deterioration of long-term prognosis in cirrhotic patients: Metaanalysis of three randomized controlled trials. Cancer. 91:2378–2385. 2001. View Article : Google Scholar : PubMed/NCBI

8 

Katsura Y, Wada H, Kobayashi S, Marubashi S, Eguchi H, Tanemura M, Umeshita K, Wakasa K, Doki Y, Mori M and Nagano H: [A case of complete response to interferon-alpha and S-1 combination therapy for multiple pulmonary recurrences of hepatocellular carcinoma after hepatic resection]. Gan To Kagaku Ryoho. 38:2487–2489. 2011.PubMed/NCBI

9 

Oh YJ, Park YM, Kim BH, Kim MJ, Cho JH, Cha CW, Park SJ and Yeon JW: A case of hepatocellular carcinoma with pulmonary metastases treated successfully with a combination of repeated hepatic arterial infusion epirubicin and Cisplatin chemotherapy and systemic low-dose infusion of 5-Fluorouracil. Gut Liver. 3:343–348. 2009. View Article : Google Scholar : PubMed/NCBI

10 

Kilickap S, Kars A, Hamaloglu E and Simsek H: A case of recurrent metastatic hepatocellular cancer controlled with immunotherapy and antiviral therapy following resection. Med Oncol. 26:501–505. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Tanaka K, Yamada K, Sasaki H, Kishi K, Noura S, Takachi K, Eguchi H, Miyashiro I, Ohue M, Ohigashi H, Yano M, Ishikawa O and Imaoka S: [A surgical case of solitary lymph node metastatic recurrence of hepatocellular carcinoma after hepatectomy]. Gan To Kagaku Ryoho. 33:1938–1940. 2006.PubMed/NCBI

12 

Nakamura M, Nagano H, Wada H, Ota H, Damdinsuren B, Marubashi S, Miyamoto A, Takeda Y, Umeshita K, Dono K and Monden M: A case of hepatocellular carcinoma with multiple lung, spleen, and remnant liver metastasis successfully treated by combination chemotherapy with the novel oral DPD-inhibiting chemotherapeutic drug S-1 and interferon-alpha. J Gastroenterol. 41:1120–1125. 2006. View Article : Google Scholar : PubMed/NCBI

13 

Nakamura M, Nagano H, Sakon M, Yamamoto T, Ota H, Wada H, Yoshioka S, Kato H, Damdinsuren B, Marubashi S, et al: [A case of HCC with inferior caval vein tumor thrombus and multiple pulmonary metastases that remarkably responded to combination therapy of TS-1 and interferon-alpha]. Gan To Kagaku Ryoho. 32:1824–1828. 2005.PubMed/NCBI

14 

Nakamura M, Nagano H, Sakon M, Kondo M, Yamamoto T, Ota H, Wada H, Damdinsuren B, Yang Y, Marubashi S, et al: [A case of long-term survivor with multiple pulmonary metastases of HCC after hepatic resection]. Gan To Kagaku Ryoho. 31:1939–1942. 2004.PubMed/NCBI

15 

Kanda Y, Akazawa S, Futatsugi K, Fujiki T, Saifuku K, Yamamoto K, Suzuki F, Nakajima T, Naoi Y, Muraoka M, et al: [A case of hepatocellular carcinoma (HCC) with lung metastasis which responded to chemotherapy with a single use of 1-hexylcarbamoyl-5-fluorouracil (HCFU)]. Gan To Kagaku Ryoho. 16:269–272. 1989.PubMed/NCBI

16 

Akita H, Marubashi S, Wada H, Hama N, Kawamoto K, Kobayashi S, Eguchi H, Doki Y, Mori M and Nagano H: Combination therapy with S-1 and interferon-α in hepatocellular carcinoma patients with lung metastasis. Mol Clin Oncol. 3:322–328. 2015. View Article : Google Scholar : PubMed/NCBI

17 

Jiang S, Liu Y, Wang L, Duan C and Liu M: A meta-analysis and systematic review: Adjuvant interferon therapy for patients with viral hepatitis-related hepatocellular carcinoma. World J Surg Oncol. 11:2402013. View Article : Google Scholar : PubMed/NCBI

18 

Zhang W, Song TQ, Zhang T, Wu Q, Kong DL, Li Q and Sun HC: Adjuvant interferon for early or late recurrence of hepatocellular carcinoma and mortality from hepatocellular carcinoma following curative treatment: A meta-analysis with comparison of different types of hepatitis. Mol Clin Oncol. 2:1125–1134. 2014. View Article : Google Scholar : PubMed/NCBI

19 

Huang TS, Shyu YC, Chen HY, Yuan SS, Shih JN and Chen PJ: A systematic review and meta-analysis of adjuvant interferon therapy after curative treatment for patients with viral hepatitis-related hepatocellular carcinoma. J Viral Hepat. 20:729–743. 2013. View Article : Google Scholar : PubMed/NCBI

20 

Yang S, Lin Q, Lin W, Hu W and Wang G: Effect of adjuvant interferon therapy on hepatitis B virus-related hepatocellular carcinoma: A systematic review. World J Surg Oncol. 14:1592016. View Article : Google Scholar : PubMed/NCBI

21 

Eun JR, Lee HJ, Moon HJ, Kim TN, Kim JW and Chang JC: Hepatic arterial infusion chemotherapy using high-dose 5-fluorouracil and cisplatin with or without interferon-alpha for the treatment of advanced hepatocellular carcinoma with portal vein tumor thrombosis. Scand J Gastroenterol. 44:1477–1486. 2009. View Article : Google Scholar : PubMed/NCBI

22 

O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB and Laurence A: The JAK-STAT pathway: Impact on human disease and therapeutic intervention. Annu Rev Med. 66:311–328. 2015. View Article : Google Scholar : PubMed/NCBI

23 

Quiroga AD, de Lujan Alvarez M, Parody JP, Ronco MT, Carnovale CE and Carrillo MC: Interferon-alpha2b (IFN-alpha2b)-induced apoptosis is mediated by p38 MAPK in hepatocytes from rat preneoplastic liver via activation of NADPH oxidase. Growth Factors. 27:214–227. 2009. View Article : Google Scholar : PubMed/NCBI

24 

Maeda S, Wada H, Naito Y, Nagano H, Simmons S, Kagawa Y, Naito A, Kikuta J, Ishii T, Tomimaru Y, et al: Interferon-α acts on the S/G2/M phases to induce apoptosis in the G1 phase of an IFNAR2-expressing hepatocellular carcinoma cell line. J Biol Chem. 289:23786–23795. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Schmeisser H, Bekisz J and Zoon KC: New function of type I IFN: Induction of autophagy. J Interferon Cytokine Res. 34:71–78. 2014. View Article : Google Scholar : PubMed/NCBI

26 

Comet NR, Aguiló JI, Rathoré MG, Catalán E, Garaude J, Uzé G, Naval J, Pardo J, Villalba M and Anel A: IFNα signaling through PKC-θ is essential for antitumor NK cell function. Oncoimmunology. 3:e9487052014. View Article : Google Scholar : PubMed/NCBI

27 

Lapenta C, Donati S, Spadaro F, Castaldo P, Belardelli F, Cox MC and Santini SM: NK cell activation in the antitumor response induced by IFN-α dendritic cells loaded with apoptotic cells from follicular lymphoma patients. J Immunol. 197:795–806. 2016. View Article : Google Scholar : PubMed/NCBI

28 

Hervas-Stubbs S, Mancheño U, Riezu-Boj JI, Larraga A, Ochoa MC, Alignani D, Alfaro C, Morales-Kastresana A, Gonzalez I, Larrea E, et al: CD8 T cell priming in the presence of IFN-α renders CTLs with improved responsiveness to homeostatic cytokines and recall antigens: Important traits for adoptive T cell therapy. J Immunol. 189:3299–3310. 2012. View Article : Google Scholar : PubMed/NCBI

29 

Pacella I, Timperi E, Accapezzato D, Martire C, Labbadia G, Cavallari EN, D'Ettorre G, Calvo L, Rizzo F, Severa M, et al: IFN-α promotes rapid human Treg contraction and late Th1-like Treg decrease. J Leukoc Biol. 100:613–623. 2016. View Article : Google Scholar : PubMed/NCBI

30 

Wang J, Zhu CP, Hu PF, Qian H, Ning BF, Zhang Q, Chen F, Liu J, Shi B, Zhang X and Xie WF: FOXA2 suppresses the metastasis of hepatocellular carcinoma partially through matrix metalloproteinase-9 inhibition. Carcinogenesis. 35:2576–2583. 2014. View Article : Google Scholar : PubMed/NCBI

31 

Martin MD, Carter KJ, Jean-Philippe SR, Chang M, Mobashery S, Thiolloy S, Lynch CC, Matrisian LM and Fingleton B: Effect of ablation or inhibition of stromal matrix metalloproteinase-9 on lung metastasis in a breast cancer model is dependent on genetic background. Cancer Res. 68:6251–6259. 2008. View Article : Google Scholar : PubMed/NCBI

32 

Wang L, Wu WZ, Sun HC, Wu XF, Qin LX, Liu YK, Liu KD and Tang ZY: Mechanism of interferon alpha on inhibition of metastasis and angiogenesis of hepatocellular carcinoma after curative resection in nude mice. J Gastrointest Surg. 7:587–594. 2003. View Article : Google Scholar : PubMed/NCBI

33 

Sun HC, Tang ZY, Wang L, Qin LX, Ma ZC, Ye QH, Zhang BH, Qian YB, Wu ZQ, Fan J, et al: Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: A randomized clinical trial. J Cancer Res Clin Oncol. 132:458–465. 2006. View Article : Google Scholar : PubMed/NCBI

34 

Gong W, Zhang GM, Liu Y, Lei Z, Li D, Yuan Y, Huang B and Feng ZH: IFN-gamma withdrawal after immunotherapy potentiates B16 melanoma invasion and metastasis by intensifying tumor integrin alphavbeta3 signaling. Int J Cancer. 123:702–708. 2008. View Article : Google Scholar : PubMed/NCBI

35 

Hiramatsu N, Yamada R and Takehara T: The suppressive effect of nucleos(t)ide analogue treatment on the incidence of hepatocellular carcinoma in chronic hepatitis B patients. J Gastroenterol Hepatol. 31:546–552. 2016. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

September-2018
Volume 16 Issue 3

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Wang F, Lv H, Li Y, Han T, Liu H, Jia K, Liu F, Gao Y and Wang F: Complete cure of a patient with HBV‑associated hepatocellular carcinoma with lung metastasis using interferon and survival up to 108 months: A case report and literature review. Oncol Lett 16: 2979-2988, 2018.
APA
Wang, F., Lv, H., Li, Y., Han, T., Liu, H., Jia, K. ... Wang, F. (2018). Complete cure of a patient with HBV‑associated hepatocellular carcinoma with lung metastasis using interferon and survival up to 108 months: A case report and literature review. Oncology Letters, 16, 2979-2988. https://doi.org/10.3892/ol.2018.9033
MLA
Wang, F., Lv, H., Li, Y., Han, T., Liu, H., Jia, K., Liu, F., Gao, Y., Wang, F."Complete cure of a patient with HBV‑associated hepatocellular carcinoma with lung metastasis using interferon and survival up to 108 months: A case report and literature review". Oncology Letters 16.3 (2018): 2979-2988.
Chicago
Wang, F., Lv, H., Li, Y., Han, T., Liu, H., Jia, K., Liu, F., Gao, Y., Wang, F."Complete cure of a patient with HBV‑associated hepatocellular carcinoma with lung metastasis using interferon and survival up to 108 months: A case report and literature review". Oncology Letters 16, no. 3 (2018): 2979-2988. https://doi.org/10.3892/ol.2018.9033