Interferon Maintenance Therapy Research Articles

Maintenance interferon therapy in chronic hepatitis C patients who failed initial antiviral therapy: A meta-analysis.

Objectives:To evaluate the effect of pegylated interferon maintenance therapy in patients with chronic hepatitis C who failed initial antiviral therapy.Methods:This is a meta-analysis of 6 randomized controlled trials that met the eligibility criteria. In all, 2438 chronic hepatitis C patients who failed to achieve sustained virologic response after initial treatment with pegylated interferon and ribavirin (antiviral therapy nonresponders or relapsers) were enrolled; 1237 patients received maintenance therapy (Maintenance group) and 1201 received no treatment (Observation group).Results:The pooled analyses found that patients in the Maintenance group had a significantly higher rate of normal alanine aminotransferase than did patients in the Observation group (pooled odds ratio [OR] 4.436, 95% confidence interval [CI] 1.225–16.064, P = .023), but there was no significant difference between the 2 groups in the incidence of hepatocellular carcinoma (pooled OR 0.872, 95% CI 0.501–1.519, P = .630), or the mortality rate (pooled OR 1.564, 95% CI 0.807–3.032, P = .185).Conclusions:Interferon-based maintenance therapy in patients with chronic hepatitis C who failed initial antiviral therapy improved liver inflammation as indicated by blood chemistry (alanine aminotransferase).

Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?

Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go?

Risk of Hepatocellular Carcinoma Development in Cases of Hepatitis C Treated by Long-Term, Low-Dose PEG-IFNα-2a

Objective: Increasing evidence suggests the efficacy of maintenance therapy with interferon (IFN) for chronic hepatitis C (CHC) in reducing the risk of hepatocellular carcinoma (HCC). The aim of this study was to determine clinical characteristics on the risk of occurrence of HCC in CHC patients receiving maintenance IFN therapy. Methods: A total of 55 patients were treated in a single center with PEG-IFNα-2a monotherapy for CHC and evaluated for variables predictive of the occurrence of HCC. Results: The cumulative incidences of HCC were 0.092, 0.117 and 0.161 at 3, 5 and 7 years, respectively. Serum ALT level (>40 IU/l) in the 6th month after commencement of IFN therapy and BMI >25 were associated with shorter time-to-HCC emergence using multivariate analysis (relative risk 16.034, p = 0.01 for ALT >40 IU/l; relative risk 6.020, p = 0.026 for BMI >25, respectively). The IL28B SNP was extracted as a significant factor for the occurrence of HCC. Conclusions: Maintenance therapy with the use of long-term low-dose PEG-IFNα-2a is effective for preventing HCC occurrence irrespective of the IL28B SNP, at least for a subset of CHC patients. The initial response of serum ALT levels and BMI provides a prognostic value for determining the risk of developing HCC later in life.

Effect of branched-chain amino acid-enriched nutritional supplementation on interferon therapy in Japanese patients with chronic hepatitis C virus infection: a retrospective study

BackgroundThe aims of this study were to evaluate the effects of nutritional supplementation with branched-chain amino acids (BCAA) with zinc component (Aminofeel®) on adherence to and outcome of therapy in patients treated with interferon (IFN) for chronic hepatitis C and cirrhosis and to determine whether to recommend the supplement.MethodsIn this retrospective study, 51 patients who received IFN therapy were investigated among 203 consecutive patients who visited our hospital and were advised regarding the potential benefit of taking Aminofeel®. Each patient was free to choose whether to purchase and take Aminofeel®.ResultsTwenty four patients (group 1-A) took Aminofeel® during standard IFN therapy and 13 (group 1-B) did not. Low-dose, long-term IFN (maintenance) therapy, mainly peglated (Peg)-IFN alpha 2a, was administered to 14 patients who were difficult to treat, because of no effect or harmful side effects with standard IFN therapy, and who had advanced liver fibrosis. Among the 14, 11 patients (group 2-A) took Aminofeel® and 3 (group 2-B) did not. The prevalence of obesity was significantly higher (P=0.04) in group 1-A than in group 1-B. The rate of adherence to IFN therapy was higher in group 1-A (83.3%) than in group 1-B (53.8%, P=0.05). There were no significant differences between the two groups in the rates of sustained virological response (SVR) to IFN therapy. According to multivariate analysis, two factors, SVR and intake of Aminofeel®, were associated with successful adherence to IFN therapy. The adjusted odds ratios for these two factors were 13.25 and 12.59, respectively, and each was statistically significant. The SVR rate of maintenance IFN therapy was in 18.2% group 2-A and 0% in group 2-B.ConclusionOur data show that BCAA intake is useful for adherence to and effect of IFN therapy for patients with chronic hepatitis C. Nutritional supplementation with BCAA seems to be useful for HCV-infected patients receiving IFN therapy because it is impossible to introduce standard treatment for all patients among Japan's aging population.

Effects of interferon therapy on development of hepatocellular carcinoma in patients with hepatitis C‐related cirrhosis: A meta‐analysis of randomized controlled trials

The role of interferon (IFN) therapy on prevention of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related cirrhosis remains controversial. This meta-analysis aimed to determine whether IFN therapy reduced the incidence of HCC in HCV-related cirrhotic patients. We performed a meta-analysis including eight randomized controlled trials (RCT) (a total of 1505 patients) to assess the effect of IFN therapy on prevention of HCC in patients with HCV-related cirrhosis. The pooled odds ratios (OR) were calculated using a random or fixed effects model. Our results showed that IFN therapy significantly decreased the overall HCC incidence in HCV-related cirrhotic patients (OR, 0.29; 95% confidence interval [CI], 0.10-0.80; P = 0.02). HCC risk in patients who failed to achieve sustained virological response (SVR) in the initial IFN-based treatment was also reduced by maintenance IFN therapy (OR, 0.54; 95% CI, 0.32-0.90; P = 0.02). Subgroup analysis indicated that IFN therapy decreased HCC incidence in HCV-related cirrhotic patients during long-term follow up (>48 months) evidently (OR, 0.25; 95% CI, 0.09-0.67; P = 0.006). However, subgroup analysis of four RCT with short-term follow up (≤48 months) did not demonstrate the significant difference in HCC incidence between IFN-treated cirrhotic patients and controls (OR, 0.78; 95% CI, 0.39-1.55; P = 0.48). The present study suggested that IFN therapy could efficiently reduce HCC development in patients with HCV-related cirrhosis; this effect was more evident in the subgroup of patients with long-term follow up (>48 months). Patients who received maintenance IFN therapy had a lower risk of HCC than controls.

Effects of interferon treatment on development and progression of hepatocellular carcinoma in patients with chronic virus infection: A meta‐analysis of randomized controlled trials

Available literature on the effects of interferon (IFN) treatment on development and progression of hepatocellular carcinoma (HCC) in patients with chronic virus infection reports controversial results. The primary objective of this meta-analysis was to evaluate the effect of IFN on HCC risk in patients with chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection; IFN's efficacy on local tumor progression and survival of advanced HCC patients was also assessed. All randomized controlled trials (RCTs) comparing IFN with no antiviral treatment were selected. Finally, we identified 11 RCTs including 1,772 patients, who met our inclusion criteria to perform this meta-analysis. Our analysis results showed that IFN significantly decreased the overall HCC incidence in HCV-infected patients [relative risk (RR)=0.39; 95% confidence interval (CI)=0.26-0.59; p=0.000], subgroup analysis indicated that IFN decreased HCC incidence in HCV-related cirrhotic patients evidently (RR=0.44; 95% CI=0.28-0.68; p=0.000); but HCC incidence in nonresponders to initial antiviral therapy did not reduce by maintenance IFN therapy (RR=0.96; 95% CI=0.59-1.56; p=0.864). Analysis results also demonstrated that IFN did not significantly affect the overall rate of HCC in HBV-infected patients although there was a trend favoring IFN therapy (RR=0.23; 95% CI=0.05-1.04; p=0.056). Besides, IFN did not improve one-year overall survival of advanced HCC patients significantly (RR=1.61; 95% CI=0.96-2.69; p=0.072); however, a quantitative analysis on local tumor progression could not be performed owing to lack of unified definitions among trials included in our study. By this meta-analysis, we conclude that IFN therapy is effective in reducing overall HCC risk in chronic HCV-infected patients; using it in this subpopulation seems promising, but its administration in other subpopulations still requires further exploration.

The Role of Interferon Therapy in Patients with Hepatocellular Carcinoma

Interferon (IFN) not only may have antiviral properties against hepatitis C, but also may reduce the risk of hepatocellular carcinoma (HCC) through anticarcinogenic properties or indirectly by antifibrotic effects. Because patients with chronic hepatitis C and cirrhosis are at risk for HCC, IFN was used to prevent or treat HCC in patients with hepatitis C. Studies demonstrate that the risk of HCC in hepatitis C patients who are sustained viral responders is substantially reduced but not eliminated. The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis trial demonstrated that maintenance therapy with IFN does not reduce the risk of HCC in patients with bridging fibrosis or cirrhosis. Other studies suggest the risk of HCC is reduced with IFN maintenance therapy in older patients or in patients whose α-fetoprotein levels decline. A randomized clinical trial demonstrated IFN therapy is not effective against HCC. Few studies suggest IFN may reduce the risk of recurrent HCC or reduce tumor burden after ablation or resection. Larger trials are needed to determine if IFN can prevent tumor recurrence after resection or locoregional therapy in patients with hepatitis C cirrhosis and HCC.

Sustained Long-Term Antiviral Maintenance Therapy in HCV/HIV-Coinfected Patients (SLAM-C)

Hepatitis C virus (HCV)/HIV coinfection treatment is suboptimal with low sustained viral response rates to standard therapies. A multicenter randomized clinical trial designed to assess the efficacy/safety of pegylated interferon maintenance therapy was performed by the National Institutes of Health-funded AIDS Clinical Trials Group network. HCV treatment-naive and nonresponding interferon-experienced subjects with confirmed HCV and HIV, CD4 >200 cells per cubic millimeter, and at least stage 1 fibrosis were enrolled and treated for 12 weeks with pegylated interferon alfa 2a 180 mcg per week (PEG) + weight-based ribavirin to determine response status. Nonresponder subjects (failure to clear HCV RNA or achieve 2-log drop) underwent liver biopsy and were randomized to receive full dose PEG or observation only for 72 weeks. Paired biopsies were evaluated by a central pathologist. Three hundred thirty subjects were enrolled; median age was 48 years; 43% white, 37% black, non-Hispanic; 83% male; CD4+ 498 cells per cubic millimeter; 32% were interferon experienced; 74% had entry HIV RNA <50 copies per milliliter. early virologic responder was observed in 55.9% and 42.5% achieved complete Early Viral Response (cEVR). A planned interim analysis of occurred when 84 subjects were randomized. With data on 40 paired biopsies available, a safety monitoring board stopped the trial due to lack of fibrosis progression (median = 0 Metavir units/year) in the observation arm. Lack of fibrotic progression in the control arm was unexpected and may represent a short-term PEG/ribavirin therapy effect, high levels of HIV viral suppression, and use of antiretroviral regimens that may be less toxic than prior generations of therapy.

Sustained long‐term remissions with weekly interferon maintenance therapy in hairy cell leukemia

This study evaluates the efficacy of weekly α-interferon (IFN) maintenance therapy in hairy cell leukaemia (HCL), a disease that remains incurable. Nine patients (six male, three female, aged 41-69 yrs) with hairy cell leukaemia (HCL) received IFN 3mU s.c. once weekly as long-term maintenance therapy after achieving optimal clinical and hematological response to initial therapy with thrice weekly IFN. Eight of the nine patients are in a state of sustained response at 3-17 years (median 12 years). Our results are similar to those from three previous studies using long-term IFN maintenance therapy, bringing the total number of patients in sustained remission to 118. We hope these reports will lead to a multi-centre, phase III study of IFN maintenance therapy (including pegylated IFN, given less frequently) in HCL patients achieving optimal response to initial therapy, be it IFN or a purine analogue.

Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma

Thalidomide maintenance therapy after stem cell transplantation resulted in increased progression-free survival and overall survival in a few trials, but its role in non-transplant eligible patients with multiple myeloma remains unclear. This study assessed the impact of thalidomide-interferon in comparison to interferon maintenance therapy in elderly patients with multiple myeloma. Of 289 elderly patients with multiple myeloma who were randomized to thalidomide-dexamethasone or melphalan-prednisolone induction therapy, 137 finally completed 9 cycles of induction therapy with stable disease or better and thereby qualified for maintenance treatment. Of these, 128 have been randomized to either thalidomide-interferon or interferon alone. Primary study endpoints were progression-free survival and response rates; secondary endpoints were overall survival, toxicity and quality of life. Thalidomide-interferon maintenance therapy led to a significantly longer progression-free survival compared to interferon (27.7 vs. 13.2 months, P=0.0068), but overall survival was similar in both groups (52.6 vs. 51.4 months, P=0.81) and did not differ between patients aged 75 years or older, or younger patients (P=0.39). Survival after disease progression tended to be shorter in patients on thalidomide-interferon maintenance therapy (P=0.056). Progression-free survival and overall survival tended to be shorter in patients with adverse cytogenetic (FISH) findings compared to the standard risk group but differences were not significant (P=0.084 and P=0.082, respectively). Patients on thalidomide-interferon presented with more neuropathy (P=0.0015), constipation (P=0.0004), skin toxicity (P=0.0041) and elevated creatinine (P=0.026). Thalidomide plus interferon maintenance therapy increased progression-free survival but not overall survival and was associated with slightly more toxicity than maintenance with interferon alone. (ClinicalTrials.gov Identifier: NCT00205751).

Erratum to: The Role of Interferon Therapy in Patients With Hepatocellular Carcinoma

Interferon (IFN) not only may have antiviral properties against hepatitis C, but also may reduce the risk of hepatocellular carcinoma (HCC) through anticarcinogenic properties or indirectly by antifibrotic effects. Because patients with chronic hepatitis C and cirrhosis are at risk for HCC, IFN was used to prevent or treat HCC in patients with hepatitis C. Studies demonstrate that the risk of HCC in hepatitis C patients who are sustained viral responders is substantially reduced but not eliminated. The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis trial demonstrated that maintenance therapy with IFN does not reduce the risk of HCC in patients with bridging fibrosis or cirrhosis. Other studies suggest the risk of HCC is reduced with IFN maintenance therapy in older patients or in patients whose α-fetoprotein levels decline. A randomized clinical trial demonstrated IFN therapy is not effective against HCC. Few studies suggest IFN may reduce the risk of recurrent HCC or reduce tumor burden after ablation or resection. Larger trials are needed to determine if IFN can prevent tumor recurrence after resection or locoregional therapy in patients with hepatitis C cirrhosis and HCC.

New therapeutic strategies needed for advanced disease

Approximately 50% of patients with chronic hepatitis C fail to achieve a sustained virological response to standard therapy with pegylated interferon and ribavirin. Progression to advanced liver disease (which may lead to hepatic decompensation, hepatocellular carcinoma, and death) is common in these patients, but can low-dose pegylated interferon maintenance therapy improve outcomes?

Long-Term Interferon Maintenance Therapy Improves Survival in Patients with HCV-Related Hepatocellular Carcinoma after Curative Radiofrequency Ablation

Objective: To assess whether low-dose, long-term maintenance interferon (IFN) therapy inhibits recurrence after complete ablation of hepatocellular carcinoma (HCC) and improves patient survival. Methods and Patients: From June 1999 through May 2006, a total of 127 HCC cases that met the requirements of both tumor diameter 3 cm or less, and number of tumors three or fewer, were curatively treated by radiofrequency ablation therapy (RFA). Among them, 43 patients received three million IU of IFN-α2b twice per week or pegylated IFN-α2a 90 µg once per week or once per 2 weeks without discontinuation (IFN maintenance group). The remaining 84 patients, whose sex, age, and platelet counts were randomly matched to those of the IFN maintenance group, did not receive IFN treatment (control group). Results: Cumulative first, second, and third recurrence rates were significantly reduced in the IFN maintenance group compared with the control group by Kaplan-Meier estimate. The 5-year survival rate was 66% for the control group and 83% for the IFN maintenance group (p = 0.004). Multivariate analysis using the Cox proportional hazards model identified IFN maintenance therapy as an independent risk factor for survival, and the risk ratio was 0.21 (95% CI: 0.05–0.73). In conclusion, low-dose, long-term maintenance IFN therapy after curative RFA therapy of HCC significantly inhibits recurrence, and consequently improves patient survival.

Thalidomide-Dexamethasone vs. Melphalan-Prednisone as First Line Treatment and Thalidomide-Interferon vs. Interferon Maintenance Therapy in Elderly Patients with Multiple Myeloma.

Thalidomide-Dexamethasone (TD) is an active regimen both in patients (pts) with relapsing/refractory and in untreated pts with multiple myeloma (MM). Here we compare TD with standard Melphalan-Prednisone (MP) in previously untreated elderly pts with MM. 274 pts have been enrolled (median age: 72 yrs, stage I: 9 (3%), stage II: 84 (31%), stage III: 179 (65%). Pts were randomized to T 200mg/day and D 40mg, days 1–4 and 15–18 (on odd cycles) and days 1–4 (on even cycles) or M 0.25mg/kg days 1–4 and P2mg/kg days 1–4, q 4–6 weeks. T should be dosed up to 400mg/day, if feasible. Pts achieving response or SD were randomized to maintenance therapy either with T (≤200mg/day)-Interferon-a2b (IFN, 3Mega U, TIW) or IFN (3Mega U/TIW). Zoledronic acid (4mg) was administered monthly to all pts during the entire treatment period. Response is defined according Blade's criteria, plus nCR defined as IF positive or >90%↓ in PP and VGPR defined as >75% ↓reduction in PP. 231 pts are evaluable per protocol. Best response to TD: CR (14%) nCR 17%, VGPR 17%, PR 21%, yielding an ORR (CR-PR) of 68%. Best response to MP: CR 7%, nCR 8%, VGPR 14%, PR 22%; ORR 51% (ORR in TD vs. MP p=.0044). Time to response and time to best response were shorter in the TD (6, 16 weeks, respectively) compared to the MP group (16, 25 weeks, respectively; p<.001, p<.002, respectively).There was a tendency for more early treatment discontinuations in the TD arm (15 vs. 11, p=.416) and a higher mortality during the first treatment year (31 vs. 17, p=.026). Pts treated with MP showed a tendency for longer EFS (median: 43 vs. 25mos; p<.07) and had sign. longer OS compared to those on TD (median: 58 vs. 45mos;p=.029). A retrospective comparison of pts ≤ aged 72 showed no difference in OS (median: 57.9 vs. 50 mos, p<.186) but OS was longer in pts >72 yrs treated with MP (median: 46.5.9 vs. 25.4, p<.0625). Maintenance treatment in the 108 pts randomized to either T-IFN, or IFN only, did not result in a sign. difference in OS (from start of maintenance: not reached vs. 41.1 mos, p<.95). Pts on MP had a higher incidence of G 3–4 leucopenia (14% vs. 3%; p< .0001), while for thrombocytopenia only a tendency for a higher frequency was noted. Pts on TD had more G 2–3 neuropathy (28% vs. 10%, p<.001), constipation (30% vs. 10%, p<.001), psychological toxicity (18% vs. 6%, p<.0006), and a tendency for a higher rate of skin toxicity (9% vs. 5%, p=.069), and infections (23% vs. 16%, p<.12) compared to those on MP. The cumulative incidence of DVTs was 15% in pts on TD and 6% in those on MP (p=.089). In conclusion, TD treatment resulted in sign. higher rate of CR/nCR and ORR, a sign. shorter time to response and to best response. Pts on TD had similar EFS but sign. shorter OS. This was particularly true in pts aged >72 years but not in those aged ≤72 who showed similar OS with TD and MP. Pts on TD had more neuropathy, DVT, psychological toxicity, and a higher rate of early treatment discontinuations, while haematological toxicity was higher in pts treated with MP.

Outcomes of Nontransplant Potentially Curative Therapy for Early-Stage Hepatocellular Carcinoma in Child-Pugh Stage A Cirrhosis Is Comparable with Liver Transplantation

Background: This study was undertaken to assess the outcome of potentially curative therapy for early-stage hepatocellular carcinoma (HCC) in patients with Child-Pugh stage A cirrhosis as well as to investigate the impact of low-dose interferon (IFN) therapy after curative therapy on survival. Methods: This study retrospectively evaluated clinical outcomes in a cohort of 224 Child-Pugh stage A cirrhotic patients who received either resection (53 cases) or radiofrequency ablation (RFA: 171 cases) for HCC within Milan criteria. Thirty patients were treated with low-dose maintenance IFN therapy after initial curative therapy. The median follow-up period was 36.7 months. Results: The 5-year survival rate of all patients was 74.9%, with similar rates for the resection and RFA groups (70.4 vs. 76.8%; p = 0.561). The 5-year HCC recurrence rate was higher in the RFA group than the resection group (85.3 vs. 73.2%; p = 0.012). The maintenance IFN-treated group maintained their liver function within Child-Pugh stage A for a significantly longer time (median time 36.9 vs. 32.2 months; p = 0.0025). Conclusion: The 5-year outcomes of resection and RFA in patients with Child-Pugh stage A cirrhosis and early stage HCC were comparable with liver transplantation. Low-dose, long-term maintenance IFN therapy after curative therapy was significantly beneficial on survival.

Standard Chemotherapy Compared With High-Dose Chemoradiotherapy for Multiple Myeloma: Final Results of Phase III US Intergroup Trial S9321

Results of a prospective randomized trial conducted by the Intergroupe Francais du Myélome (IFM 90) indicated that autologous hematopoietic cell-supported high-dose therapy (HDT) effected higher complete response rates and extended progression-free survival (PFS) and overall survival (OS) compared with standard-dose therapies (SDT) for patients with multiple myeloma (MM). In 1993, three North American cooperative groups launched a prospective randomized trial (S9321) comparing HDT (melphalan [MEL] 140 mg/m2 plus total-body irradiation 12 Gy) with SDT using the vincristine, carmustine, MEL, cyclophosphamide, and prednisone regimen. Responders on both arms (> or = 75%) were randomly assigned to interferon (IFN) or no maintenance treatment. With a median follow-up time of 76 months, no differences were observed in response rates between the two study arms (HDT, n = 261 patients; SDT, n = 255 patients). Similarly, PFS and OS durations did not differ between the HDT and SDT arms, with 7-year estimates of PFS of 17% and 16%, respectively, and OS of 37% and 42%, respectively. Of 242 patients achieving at least 75% tumor reduction, no difference was observed in PFS or OS among the 121 patients randomly assigned to IFN and the 121 patients randomly assigned to no maintenance therapy. Among 157 patients relapsing on SDT, 87 received a salvage autotransplantation; their median survival time of 30 months was only slightly better than the survival time of the remaining patients who were managed with further SDT (23 months; P = .13). The HDT and SDT regimens used in S9321 yielded comparable response rates and PFS and OS durations. IFN maintenance therapy did not benefit patients who achieved > or = 75% tumor reduction on either arm.

Total Therapy 2 (No Thalidomide Arm, TT2-) Is Superior to Total Therapy 1 (TT1) for Newly Diagnosed Multiple Myeloma (MM): Doubling 4-Yr Survival among Patients with Cytogenetic Abnormalities (CA) Due to Consolidation Chemotherapy (CCT) and DEX Maintenance.

Background: TT2 introduced T into the frontline therapy for MM in a randomized phase III trial design (ASCO 2005). In comparison to TT1, TT2 applied: (1) more intensive chemotherapy for induction prior to and introduced CCT after melphalan 200mg/sqm-based tandem autotransplants, designed to improve survival in high-risk patients with CA; (2) DEX pulsing was added during the 1st year of interferon (IFN) maintenance therapy. We now report on the outcome of patients treated on the “no thalidomide” arm of TT2 (TT2-) in comparison to TT1, in order to evaluate the effect of dose-intensification during induction and post-transplant therapy.Patients and Methods: 231 patients were enrolled in TT1 (median follow-up, 11yr) and 345 in TT2- (median follow-up, 3.5yr). Completion rates of 1st/2nd transplants were 195/165 (84%/71%) with TT1 and 292/235 (85%/68%) with TT2-. In TT2-, 64% started CCT and 36% received DEX consolidation (when platelets failed to recover or no benefit was documented from induction DCEP). TT2- and TT1 were compared in terms of pre-transplant-1 and final CR rates (intent-to treat), EFS/OS from treatment start, 1st transplant and from last (2nd or 1st) transplant. EFS and OS were examined in the context of baseline prognostic variables including CA.Results: Compared to TT1, TT2- induced similar pre-Tx1 CR rates (11% vs 12%, p=0.8) and final CR rates (41.3% vs 40.7%, p=0.9). The median onset of CR was 8.9mo for TT2 vs 8.4mo for TT1 (p=0.4). 5-year EFS/OS were 45%/63% with TT2- vs 28%/57% with TT1 (p<0.001/p=0.06). 4-yr post-transplant-1 EFS/OS were 48%/65% with TT2- vs 28%/56% with TT1 (p<0.001/p=0.02); 4-yr post-transplant-2 EFS/OS were 46%/64% with TT2- and 31%/50% with TT1 (both p=0.01). Pre-study CA, high LDH (>=190U/L), and low Hb (<10g/dL) were independently, significantly associated with poorer post-transplant-2 EFS and OS (p<0.05); independent of these factors, TT2- improved post-transplant-2 EFS and OS compared to TT1 (p<0.001/p=0.033). In the presence of CA, TT2- with CCT vs TT2- with DEX improved 4-yr OS (measured from a 6-mo landmark post-transplant-2) from 37% (similar to 39% with TT1 [no DEX or CCT]) to 78%, which is comparable to the 65% for TT1 without CA.Conclusion: In this historical comparison of TT1 with TT2-, the more intensive induction chemotherapy with TT2- did not improve CR. However, post-transplant CCT benefited the 1/3 of patients with CA, doubling 4-yr post-transplant OS in comparison with TT1 in this high-risk subgroup. A phase 3 randomized trial addressing the CCT concept is warranted. [Display omitted]

Comparison of Interferon Versus Thalidomide Versus RIC Allotransplant for Maintenance /Consolidation Therapy after Autologous Stem Cell Transplantation in Patients with Multiple Myeloma: A Single Center Experience.

High dose chemotherapy (HDT) with autologous stem cell transplantation has improved response rates and survival of patients with multiple myeloma. However the majority of patients suffer from relapse. Therefore, in this retrospective study we evaluated the impact of maintenance therapy with either thalidomide or interferon on the progression-free survival (PFS) after HDT and compared these results with a planned allogeneic transplant with reduced intensity conditioning (RIC) as consolidation therapy after HDT.We analysed 95 patients with a median age of 55 years who were treated at our institution in 2001–2005 with the diagnosis of stage III myeloma. Melphalan 200 mg/m2 was used as conditioning regimen followed by autologous stem cell transplantation. Interferon was given at a dose of 1.0 to 4.5 million U three times a week and the daily dose of thalidomide was 100 to 400 mg according to the individual tolerance of side effects. Allotransplants were performed with HLA-identical sibling donors after fludarabin 90 mg/m2 and TBI (2Gy) conditioning. In median 3.8 months after single HDT patients received either a RIC allotransplant (n=14) or maintenance therapy with thalidomide (n=39) or interferon (n=30) or no maintenance therapy (n=12). Prognostic factors such as cytogenetic abnormalities, beta-2 microglobulin, chemosensitive disease before HDT or remission status after HDT were equally distributed in all treatment groups.After a median follow-up of 33 months (range: 8–60) PFS from the start of treatment did not differ between patients after allotransplant (median not yet reached) and patients receiving thalidomide (median 50 months, p=0.8) but was significantly improved in comparison to patients who received interferon or no maintenance therapy (median 24 months, p<0.0001). Most patients who received interferon or no maintenance therapy were treated with thalidomide at the time of relapse. Therefore, we also compared the combined PFS of patients treated with interferon maintenance followed by thalidomide in first relapse with the PFS of patients treated with immediate thalidomide maintenance therapy. Most interestingly, PFS of these two treatment schedules was not different (median 50 months in both groups; p=0.9), but the time of thalidomide exposure was in median 13 months shorter for patients in the interferon treatment arm. This is important, as to date most novel therapies hold the risk of polyneuropathy and thus pre-existing polyneuropathy due to prior thalidomide therapy limits the therapeutical options during the course of disease.Analysis of overall survival showed no differences between patients in the thalidomide or the interferon treatment arm (median not reached in both groups, p=0.5), but survival was inferior with RIC allotransplant (median 44 months, p=0.02). In conclusion, thalidomide is an effective maintenance therapy which prolongs PFS after single HDT. Interferon is less effective but the treatment schedule interferon maintenance therapy followed by thalidomide at the time of relapse is equal to upfront thalidomide maintenance therapy in terms of cumulative PFS and may be less toxic. RIC allotransplant is not superior to other treatment options and thus still has to be considered an experimental treatment option.

Early Detection and Curative Treatment of Early-Stage Hepatocellular Carcinoma

The method for early detection of hepatocellular carcinoma (HCC) has been well-established in Japan by means of regularly screening patients at risk for developing HCC by using imaging and tumor markers. An important issue is the accurate characterization of nodular lesions found in cirrhotic livers. This problem has been addressed by development of imaging modalities such as ultrasonography angiography with intra-arterial injection of CO2, computed tomography during hepatic arteriography, and computed tomography during arterial portography. It is most important to differentiate the typical hemodynamic patterns of low-grade dysplastic nodule including arterial hypovascularity with preserved portal perfusion from those of HCC characterized by arterial hypervascularity with decreased portal perfusion. At present, these findings are easily obtained by contrast-enhanced phase-invasion harmonic imaging, which is a noninvasive ultrasound technology. Radiofrequency ablation is an efficient technique to curatively treat early-stage HCC. The 5-year survival rate of RFA at our institution is 76%. Although local recurrence rate after curative RFA is as low as 6.2%, the intrahepatic distant metastasis is as high as 85% at 5 years. The prevention of intrahepatic distant recurrence by maintenance interferon therapy is thus very important. The 5-year survival rate and first, second, and third recurrence rates after curative RFA in patients who had maintenance interferon therapy were much better than those in patients who did not receive interferon therapy after curative RFA. In conclusion, recent progress in screening, diagnostic, and therapeutic strategy for early-stage HCC has improved the prognosis of patients with HCC. Furthermore, advances of prognostic staging system, such as Japan Integrated Staging score, facilitate the management of HCC.

Bendamustine, vincristine and prednisone (BOP) versus cyclophosphamide, vincristine and prednisone (COP) in advanced indolent non-Hodgkin’s lymphoma and mantle cell lymphoma: results of a randomised phase III trial (OSHO# 19)

The purpose of this study was to compare the efficacy and toxicity of bendamustine, vincristine + prednisone (BOP) with a standard regimen of cyclophosphamide, vincristine + prednisone (COP) in patients with previously untreated advanced indolent non-Hodgkin's lymphoma (NHL) and mantle cell lymphoma. A total of 164 patients with follicular lymphoma (grade 1/2), mantle cell lymphoma or lymphoplasmacytic lymphoma (immunocytoma) was randomised to treatment with vincristine 2 mg (day 1) and prednisone 100 mg/m2 (days 1-5) + bendamustine 60 mg/m2 (days 1-5) or + cyclophosphamide 400 mg/m2 (days 1-5) for a total of eight 21-day cycles. The rate of complete remission was 22% with BOP and 20% with COP. The projected 5-year survival rate was 61% with BOP and 46% with COP. The BOP-associated 5-year survival advantage almost reached significance in the subgroup of patients who responded to therapy (74% vs. 56%; P = 0.05), and did reach significance in responders who did not receive interferon maintenance therapy (70% vs. 47%; P = 0.03). Toxicity was acceptable in both treatment groups, although alopecia and leucopenia were more severe with COP. Bendamustine can efficaciously and safely replace cyclophosphamide, as used in standard COP therapy, for the treatment of patients with indolent NHL and mantle cell lymphoma. Long-term survival data suggest a clinically significant benefit for patients treated with BOP.