Abstract
Background: Locoregional treatments represent a good option for patients suffering from hepatocellular carcinoma (HCC) not eligible for resection or transplantation. Locoregional approaches include a wide spectrum of therapeutic methods and hepatic intra-arterial drug infusion is also considered. Fotemustine is a chemotherapy drug usually administered intravenously according to standard administration schedules. Interferon alpha 2b (IFNα2b), a biological response modifier conventionally administered by a systemic route, has been employed in the treatment of both virus-related hepatitis and HCC. Nonetheless, both drugs can also be infused into the hepatic artery. Patients and Methods: We report on five patients with liver cancer, not suitable for conventional therapies, treated with hepatic intra-arterial administration of fotemustine in combination with IFNα2b. They received fotemustine at a dose of 30 mg/m2 and IFNα2b at a starting dose of 2,000,000 IU (increasing up to 3,000,000 IU for subsequent administrations) weekly for three consecutive weeks, followed by two weeks of rest. Results: Among the patients suffering from HCC, the first patient showed a partial response, two patients had almost stable disease and one patient was not assessable. A patient with an intrahepatic biliary tract cancer experienced disease progression. Conclusion: The therapeutic regimen used showed acceptable tolerability profiles and lack of life-threatening side-effects. Further evaluation with a larger patient cohort will be required to clarify if fotemustine and IFNα2b administered into the hepatic artery could be beneficial in treating patients with HCC.
To date, standard treatment options for patients suffering from hepatocellular carcinoma (HCC) include: liver transplantation, surgical resection, locoregional approaches (such as trans-arterial chemo-embolization (TACE), radiofrequency thermal ablation and hepatic intra-arterial chemotherapy) and antiangiogenic systemic therapy (Sorafenib tablets) (1, 2). Only a few therapeutic alternatives are available to treat patients with extensive liver tumors. Validated international guidelines provide adequate criteria to enable for the best choice to be made out of the above mentioned therapeutic modalities (3). Currently, brain tumors and melanoma are the preferential indications for fotemustine (4-6). Fotemustine can be administered alone or in combination with other anticancer agents. In fact, several studies have reported data on the combination of fotemustine with cisplatin, temozolomide, dacarbazine and interferon alpha (IFNα) (7-9). Systemic IFN administration has been widely investigated for patients with HCC but its effectiveness usually remains unsatisfactory or at least needs to be better defined (10-12). The direct infusion of IFN through the hepatic artery in patients suffering from HCC has been investigated by some research groups (13, 14). Furthermore, hepatic intra-arterial administration of fotemustine has been described as being safe for the treatment of liver metastases from both uveal melanoma and colon cancer (15-17). Here we report on first experience on five patients treated with an interferon alpha 2b (IFNα2b) and fotemustine-based combination therapy, both of which were administered through the hepatic artery.
Patients and Methods
We report the cases of patients suffering from liver cancer (HCC and intrahepatic bile duct cancer) not suitable or not responsive to standard treatments (neither sorafenib nor RFA and TACE). Furthermore, several comorbidities (cardiopathies, renal insufficiency) contraindicated antracycline or cisplatin-based therapies. The patients who met each of the following criteria were considered suitable for the treatment with hepatic intraarterial IFNα2b and fotemustine-based chemoimmunotherapy: a) patients not eligible for conventional treatments; b) liver as the only disease site; c) an adequate baseline hepatic function defined as a total bilirubin level ≤1.8 mg/dl; aspartate transaminase (AST) and alanine transaminase (ALT) <4 times the upper limits of normal, serum albumin level >2 g/dl; d) an adequate baseline bone marrow reserve defined as neutrophil count ≥1,500 per mm3, platelet count ≥100,000 μl, hemoglobin level >9 g/dl; e) adequate renal function defined as serum creatinine concentration <1.7 mg/dl; f) liver involvement <60%; g) performance status (PS) <2, according to the ECOG scale (18). Patients were excluded if they had one or more of the following: a) evidence of complete portal vein thrombosis; b) prothrombin time (PT) prolonged by more than 5 s above the normal control; c) refractory ascites; d) previous esophageal varices bleeding. Tumors were assessed by computed tomography (CT). Informed consent, according to institutional regulations, was obtained from all the patients prior to start of treatment. The five eligible patients underwent transaxillary or transfemoral implantation of a conventional port–catheter system for hepatic arterial infusion chemotherapy. Patients received hepatic intra-arterial fotemustine and IFNα2b on days 1, 8, 15 followed by two weeks of rest. Fotemustine dose was fixed at 30 mg/m2 in a 60 min infusion schedule. Intra-arterial IFNα2b, diluted in normal saline, was infused continuously over 48 h using an elastomeric balloon reservoir (balloon pump). The IFNα2b dose was initially fixed at 2,000,000 IU and its escalation was allowed up to 3,000,000 depending on toxicity. Dexamethasone (8 mg) was administered intra-arterially prior to the initiation of each fotemustine infusion. There was no dose reduction scheme. For patients developing grade 3 neutropenia, grade 1 thrombocytopenia (platelet count of <100,000 platelets mm3), AST and ALT serum level 4 times the upper limits of normal, or an increase to twice their initial value, total bilirubin level >1.8 mg/dl or other nonhematologic toxicity higher than grade 2, further treatment was delayed. The treatment-related adverse events were assessed by the National Cancer Institute Common Toxicity Criteria (NCI-CTC) (19). In the event of progressive disease or intolerable side-effects, treatment was stopped. Re-staging with chest and abdominal CT was performed after three cycles of therapy. Response evaluation to treatment was based on RECIST criteria (20). Tables I and II summarize the baseline parameters/characteristics, treatment and results for individual patients.
Case Reports
Case 1. An 80-year-old male, HCV-positive, was a patient with biopsy-proven HCC and suffering from cirrhosis (Child Pugh class A). Concomitant diseases, such as cardiac disfunctions (left bundle branch block, moderate reduction in left ventricular ejection fraction), and mild renal insufficiency were identified. Abdominal CT revealed multiple nodules (the largest of which was a 45 mm diameter lesion) involving both left and right liver lobes. The diffuse type HCC and the mentioned comorbidities made the patient ineligible for conventional treatments and/or cisplatin or anthracycline-based chemotherapy regimens. After failure of previous locoregional treatment, and as Sorafenib was not yet commercially available, in accordance with the decision of the health care team members, the patient was offered a hepatic intra-arterial therapy with IFNα2b in combination with fotemustine. Three cycles of the chemoimmunotherapy were delivered and the subsequent CT scan reveised significant regression of HCC lesions (Figure 1). No relevant treatment related side-effects were recorded. Subsequently, the treatment was stopped and follow-up started. To date, 39 months after the last drug infusion, the patient is still alive (83 years old) and doing well. The last CT scan, carried out a month prior to the time of writing, to check for HCC extent confirmed stable disease.
Characteristics of the eligible patients.
Case 2. The second patient was a 73-year-old female with a history of urolithiasis, previously diagnosed with mild renal insufficiency along with arterial hypertension and harboring a femoral prosthesis. She was suffering from a biopsy-proven diffuse type HCC not related to cirrhosis nor infection with hepatitis viruses. Pretreatment baseline laboratory hepatic values were within the normal range. She completed only one treatment course with hepatic intra-arterial fotemustine and IFNα2b. Subsequentely, the patient experienced skeletal complication (femoral prosthesis infection) and acute renal failure, requiring hospitalization and several hemodialysis sessions. Of further interest, an increase in bilirubin level, up to 3.43 mg/dl (reference range: 0.30-1.30 mg/dl) and AST level, up to 127 U/l (reference range: 14-50 U/l) were recorded. Thus the hepatic intra-arterial infusions were stopped, the patient's condition slowly worsened and she died four months later.
Baseline parameters, treatment and results in individual patients.
Case 3. A 60-year-old female suffering from hepatobiliary cancer, who had previously undergone several chemotherapy-based regimens with gemcitabine, cisplatin, docetaxel, capecitabine and epidoxorubicin, was offered hepatic intra-arterial therapy with IFNα2b in combination with fotemustine. No significant side-effects occurred. Due to the worsening of the disease, a response evaluation was carried out after two cycles of hepatic intra-arterial chemoimmunotherapy and the CT scan revealed disease progression. The patient died about two months later because of a rapid deterioration in liver functions.
Case 4. The patient, a 74-year-old male with a history of right bundle branch block, chronic cardiac ischemia, mild alcoholism, suffering from gallbladder lithiasis and cirrhosis (Child Pugh class A). A diffuse-type HCC (biopsy-proven) with multiple hepatic nodules was assessed by CT scan. The largest tumor mass (70 mm diameter lesion) involved both the fifth and seventh liver segments. As locoregional conventional therapies are not effective in the treatment of diffuse-type HCC, an alternative treatment was considered. Therefore, hepatic intra-arterial infusion with fotemustine and IFNα2b was proposed. The patient underwent six cycles of intra-arterial chemoimmunotherapy. No significant treatment-related toxicity was observed. Subsequent CT scan revealed minimal regression of the largest tumor nodule and stable disease in the surrounding liver tissue (Figure 2). After sorafenib was made commercially available to HCC patients, it was administered as maintenance treatment. Twelve months later, due to cancer progression, sorafenib therapy was stopped and the patient underwent chemoimmunotherapy with hepatic intra-arterial fotemustine and IFNα2b combination. At present, the patient is still receiving hepatic intra-arterial chemoimmunotherapy and lives with a cancer that has not progressed.
Case 5. A 69-year-old male, HCV-positive, with biopsy-proven diffuse type HCC previously administered sorafenib tablets. Relevant comorbities were cirrhosis (Child Pugh class A), chronic atrial fibrillation and untreated B-cell chronic lymphatic leukemia. Sorafenib administration had to be interrupted after two months due to toxicity-related complications (arterial hypertension) and cancer progression. The patient was consequently prescribed hepatic intra-arterial fotemustine in combination with IFNα2b. At baseline, serum AST and ALT levels were only slightly elevated. During the treatment, AST and ALT values further increased up to six times the upper limit of normal. Thus, because of hepatic toxicity, the IFNα2b dose was not escalated and delays in subsequent treatment sessions occurred. After three cycles of treatment, the CT scan reveised stable disease as reflected by the tumor diameter. Despite stable intrahepatic tumor size having been recorded after the sixth cycle was completed, unfortunately, the cancer progressed at an extrahepatic site (skeletal pelvis) (Figures 3 and 4). At present, the patient is still alive and a different combination chemotherapy is being administered.
Discussion
Conventional systemic chemotherapy does not offer significant benefits to patients with HCC and can be burdened by remarkable toxicity (21-23) .On the other hand, patients with diffuse-type HCC cannot be considered for conventional locoregional approaches such as TACE or radiofrequency thermal ablation (24). Moreover, severely impaired hepatic function remains a major problem when treating patients with HCC and new effective therapeutic options are not available for those who do not respond to sorafenib therapy. The theoretical advantage of intra-arterial chemotherapy over standard intravenous chemotherapy is that this sort of therapie manages to increase the regional drug levels, thus achieving a greater local activity, without an increase in general toxicity (25). Hepatic intra-arterial antiblastic drug infusion has sometimes been helpful in treating patients with HCC who cannot receive conventional therapies (26, 27). Cisplatin, anthracyclines and 5-fluorouracil are the chemotherapy drugs most commonly injected into the hepatic artery to treat patients with HCC (28-30). The biological response modifiers, such as interferons, even if administered by the hepatic intra-arterial route, might sometimes also be beneficial for HCC patients (14, 26, 31, 32). Sorafenib therapy failure and/or intolerance in HCC patients, is a problem to be tackled in the near future. Patients with well-preserved hepatic function and no evidence of extrahepatic metastases should be considered for further treatments. With regards to the utilization of fotemustine in a population of HCC patients, the following appropriate considerations should be made: At this time, fotemustine is not a chemotherapy drug of choice for HCC patients; decompensated cirrhotic patients are prone to bleeding due to thrombocytopenia and/or disturbances of clotting parameters (33); severe thrombocytopenia and leucopenia are well-recognised fotemustine-related adverse events (34); hepatic intraarterial fotemustine is a well-recognised practice (15-17). From these considerations, the authors chose to administer hepatic intra-arterial low-dose fotemustine. This method of administering fotemustine may be less toxic, reducing the risk of severe myelotoxicity and at the same time providing high intrahepatic drug levels. In our experience, intra-arterial low-dose fotemustine and FNα2b combination appeared to be a somewhat manageable therapeutic tool for the patients described here and no definitely treatment-related serious side effects were encountered in most of them. On the contrary, available literature data describe a significant risk of severe myelotoxicities (grade 3-4 neutropenia and thrombocytopenia) when almost conventional doses of systemic IFNα2b, anthracyclines or 5-fluorouracile and cisplatin based therapies are used to treat patients with HCC without providing an indisputable improvement in their survival (22, 35, 36). The reported experience within the limitations of a case series would suggest a possible role of hepatic intra-arterial fotemustine and IFNα2b in the treatment of HCC. The described drug combination may represent an additional therapeutic option for patients suffering from HCC in the absence of significant deterioration of liver function and without extrahepatic metastatic sites. Recruitment of additional patients is being taken into consideration to achieve a sufficiently large sample of HCC-affected patients and to collect more adequate data on the feasibility and safety of administering fotemustine and IFN combination by hepatic arterial infusion.
Case 1. Computed tomographic scan of the upper abdomen. a: before starting the IFN and fotemustine-based therapy, showing the largest focal hepatic lesion in the seventh segment (arrows); b: after three cycles of therapy.
Case 4. Computed tomographic scan of the upper abdomen. a: before starting IFN and fotemustine-based therapy; b: after six cycles of therapy.
Case 5. Computed tomographic scan of the upper abdomen. a: before starting IFN and fotemustine-based therapy; b: after three cycles of therapy.
Case 5. Computed tomographic scan after six cycles of therapy. a: upper abdomen; b: pelvis: the arrows indicate metastasis to the skeleton.
- Received August 23, 2011.
- Revision received November 1, 2011.
- Accepted November 2, 2011.
- Copyright© 2011 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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