Ignite Creation Date:
2024-05-05 @ 4:37 PM
Last Modification Date:
2024-10-26 @ 9:22 AM
Study NCT ID:
NCT00273247
Status:
COMPLETED
Last Update Posted:
2006-01-09
First Post:
2006-01-05
Brief Title:
Treatment With IFN After Curative Resection of HCC in HCV-Related Cirrhosis
Sponsor:
National Cancer Institute Milan
Organization:
National Cancer Institute Milan
Study Overview
Official Title:
Adjuvant α-Interferon Treatment After Resection of Hepatocellular Carcinoma in HCV-Related Cirrhosis a Randomized Trial on Prevention of Cancer Recurrence
Status:
COMPLETED
Status Verified Date:
2005-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
We conducted a randomized controlled trial of adjuvant interferon IFN therapy in patients with hepatitis-C virus HCV-related cirrhosis who underwent curative resection of hepatocellular carcinoma HCC to investigate whether IFN could reduce or delay the incidence of recurrent tumor secondarytertiary prevention of HCC Patients were randomly assigned to treatment with IFN 3MU thricewk 48 weeks vs no treatment after curative resection of HCCcontrol group
Detailed Description:
Background
Primary liver cancer hepatocellular carcinoma HCC remains a major cancer-related cause of death with an estimated incidence of 1 million cases per year worldwide and particular endemic distribution related to chronic hepatitis carriers Post-necrotic cirrhosis due to chronic infection by HBV and HCV is the leading background for HCC development with a yearly rate of 3 and a 5-year probability of survival of 20
Liver surgery resection or transplantation appears the only chance of curative treatment of the tumor but feasibility is still ranging from 15 to 30 in Western countries at time of diagnosis Several alternative treatments are available but their potential curative effects are lacking due to the absence of controlled trials
Liver resection is claimed to be feasible in order 15-30 of patients with HCC with mortality reported in major centers extremely low 5 Technical and biological devices developed in the setting of OLT can now support the limited reserve of cirrhotic livers after resection
Regulated segmentectomy is advisable with removal of the whole portal territory belonging to the tumor Single nodule tumors 5 cm and compensated cirrhosis Child class A are accepted as the best candidates for liver resection that now can be performed with minimal blood loss and minimal ischemia damage Intraoperative ultra sound examination is now routinely used as the golden standard for staging and detection of previously undiscovered neoplastic nodules Hepatic decompensation with ascites development cholestasis and variceal bleeding within three months from surgery are the main negative prognostic factors for patient survival Five years survival exceed 50 but tumor recurrences due to cirrhosis persistence could exceed 30 after three years of follow-up Several attempts to reduce recurrence through antiangiogenetic and antiproliferative agents have been proposed
In the present project a prospective randomized trial of Interferon as antiproliferative drug versus control in anti-HCV positive patients will investigate in homogeneous categories of resected tumor possible variation in the natural history and namely a reduction of recurrence rate after curative resection
Purpose and Study Design
The trial was intentionally designed in 1997 as an unresticted collection of patients with histologically proved HCC and a HCV-related cirrhosis selected for surgical resection of the tumor in 4 experienced surgical Liver Units in Italy Eligible patients were stratified on the basis of concomitant anti-core antibodies against HBV anti-HBc into two populations pure HCV HCV-RNApositive anti-HBcnegative and mixed HCVHBV HCV-RNApositive anti-HBcpositive Within each strata patients were then randomized in a 11 ratio to treatment with α-interferon IFN vs no treatment control No restriction criteria were applied to tumor stage as far as the resection of HCC was judged as potentially curative at pre-operative staging intra-operative ultrasound and post-operative pathology clearance of surgical margins
The study was originally designed for lymphoblastoid α-interferon then soon after trial approval by the NCI-Milan Scientific and Ethic Committee 98-016 the protocol was amended for allowing also the use of recombinant α-2a Roferon-A Hoffmann-La Roche Nutley NJ or α -2b interferon Intron-A Schering-Plough Kenilworth NJ The latter was eventually the preferred form Patients allocated to treatment received IFN 3 MUthrice weekly for 48 weeks starting within 6 weeks from the operation The severity of adverse events during treatment were monitored and rated Therapy was discontinued in case of life-threatening adverse event or in case of HCC recurrence during treatment For severe events other than anemia the IFN dose was reduced by 50 full dose could be resumed after the event was resolved or discontinued if the effect persisted The percentage of the total predicted dose of IFN actually assumed by each patients was recorded Patients assuming at least 80 of the total dose of IFN and treated for at least 80 of the expected duration of therapy were a priori defined as adherent to therapy
Recurrences were a priori defined as early or late whether or not they occurred within 2 years from the surgical removal of the HCC In fact early recurrence were related to intra-hepatic metastases of the primary tumor possibly missed at the time of therapy while late recurrence might be due to new cancer foci related to the persistence of HCV-related carcinogenetic factors
Primary endpoint of this randomized clinical trial RCT was recurrence-free survival RFS while the secondary endpoint were disease-specific survival DSS and overall survival OS Further secondary endpoints were the assessment of IFN tolerability in post-surgical patients and the observation of prognostic factors related to early or late recurrence Adherent patients were considered for a subgroup analysis focused on patients who effectively received the treatment designed to prevent HCC recurrence
Enrolment for the trial started on June 1998 By December 2002 the predicted sample size of 150 randomized patients was completed pure HCV 80 and mixed HCVHBV 70 The baseline clinical laboratory and tumor characteristics of the two arms and viral strata were comparable After 45 months of median follow-up the three- and five- years survival rates were 69 and 524 respectively for the control group and 773 and 636 respectively for the IFN group P 0471 At the univariate analysis tumor multiplicity 1 nodule and vascular invasion were significantly related to recurrence After adjustment of the relative weight of prognostic factors in a series of Cox models and cumulative incidence curves calculated on pattern of recurrence a benefit of IFN was observed on late recurrence occurring in the pure-HCV patients adherent to treatment hazard rate 03 95 Confidence interval009-09 P004
In conclusion although adjuvant IFN failed to show a generalized effect on prevention of HCC recurrence after curative resection it effectively reduced late recurrence due to new tumor foci in pure-HCV patient adherent to therapy ie receiving at least 80 of IFN dose for at least 80 of time
Primary liver cancer hepatocellular carcinoma HCC remains a major cancer-related cause of death with an estimated incidence of 1 million cases per year worldwide and particular endemic distribution related to chronic hepatitis carriers Post-necrotic cirrhosis due to chronic infection by HBV and HCV is the leading background for HCC development with a yearly rate of 3 and a 5-year probability of survival of 20
Liver surgery resection or transplantation appears the only chance of curative treatment of the tumor but feasibility is still ranging from 15 to 30 in Western countries at time of diagnosis Several alternative treatments are available but their potential curative effects are lacking due to the absence of controlled trials
Liver resection is claimed to be feasible in order 15-30 of patients with HCC with mortality reported in major centers extremely low 5 Technical and biological devices developed in the setting of OLT can now support the limited reserve of cirrhotic livers after resection
Regulated segmentectomy is advisable with removal of the whole portal territory belonging to the tumor Single nodule tumors 5 cm and compensated cirrhosis Child class A are accepted as the best candidates for liver resection that now can be performed with minimal blood loss and minimal ischemia damage Intraoperative ultra sound examination is now routinely used as the golden standard for staging and detection of previously undiscovered neoplastic nodules Hepatic decompensation with ascites development cholestasis and variceal bleeding within three months from surgery are the main negative prognostic factors for patient survival Five years survival exceed 50 but tumor recurrences due to cirrhosis persistence could exceed 30 after three years of follow-up Several attempts to reduce recurrence through antiangiogenetic and antiproliferative agents have been proposed
In the present project a prospective randomized trial of Interferon as antiproliferative drug versus control in anti-HCV positive patients will investigate in homogeneous categories of resected tumor possible variation in the natural history and namely a reduction of recurrence rate after curative resection
Purpose and Study Design
The trial was intentionally designed in 1997 as an unresticted collection of patients with histologically proved HCC and a HCV-related cirrhosis selected for surgical resection of the tumor in 4 experienced surgical Liver Units in Italy Eligible patients were stratified on the basis of concomitant anti-core antibodies against HBV anti-HBc into two populations pure HCV HCV-RNApositive anti-HBcnegative and mixed HCVHBV HCV-RNApositive anti-HBcpositive Within each strata patients were then randomized in a 11 ratio to treatment with α-interferon IFN vs no treatment control No restriction criteria were applied to tumor stage as far as the resection of HCC was judged as potentially curative at pre-operative staging intra-operative ultrasound and post-operative pathology clearance of surgical margins
The study was originally designed for lymphoblastoid α-interferon then soon after trial approval by the NCI-Milan Scientific and Ethic Committee 98-016 the protocol was amended for allowing also the use of recombinant α-2a Roferon-A Hoffmann-La Roche Nutley NJ or α -2b interferon Intron-A Schering-Plough Kenilworth NJ The latter was eventually the preferred form Patients allocated to treatment received IFN 3 MUthrice weekly for 48 weeks starting within 6 weeks from the operation The severity of adverse events during treatment were monitored and rated Therapy was discontinued in case of life-threatening adverse event or in case of HCC recurrence during treatment For severe events other than anemia the IFN dose was reduced by 50 full dose could be resumed after the event was resolved or discontinued if the effect persisted The percentage of the total predicted dose of IFN actually assumed by each patients was recorded Patients assuming at least 80 of the total dose of IFN and treated for at least 80 of the expected duration of therapy were a priori defined as adherent to therapy
Recurrences were a priori defined as early or late whether or not they occurred within 2 years from the surgical removal of the HCC In fact early recurrence were related to intra-hepatic metastases of the primary tumor possibly missed at the time of therapy while late recurrence might be due to new cancer foci related to the persistence of HCV-related carcinogenetic factors
Primary endpoint of this randomized clinical trial RCT was recurrence-free survival RFS while the secondary endpoint were disease-specific survival DSS and overall survival OS Further secondary endpoints were the assessment of IFN tolerability in post-surgical patients and the observation of prognostic factors related to early or late recurrence Adherent patients were considered for a subgroup analysis focused on patients who effectively received the treatment designed to prevent HCC recurrence
Enrolment for the trial started on June 1998 By December 2002 the predicted sample size of 150 randomized patients was completed pure HCV 80 and mixed HCVHBV 70 The baseline clinical laboratory and tumor characteristics of the two arms and viral strata were comparable After 45 months of median follow-up the three- and five- years survival rates were 69 and 524 respectively for the control group and 773 and 636 respectively for the IFN group P 0471 At the univariate analysis tumor multiplicity 1 nodule and vascular invasion were significantly related to recurrence After adjustment of the relative weight of prognostic factors in a series of Cox models and cumulative incidence curves calculated on pattern of recurrence a benefit of IFN was observed on late recurrence occurring in the pure-HCV patients adherent to treatment hazard rate 03 95 Confidence interval009-09 P004
In conclusion although adjuvant IFN failed to show a generalized effect on prevention of HCC recurrence after curative resection it effectively reduced late recurrence due to new tumor foci in pure-HCV patient adherent to therapy ie receiving at least 80 of IFN dose for at least 80 of time
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None