Adjuvant Interferon Therapy Research Articles

G5 Ulceration of primary melanoma and responsiveness to adjuvant interferon therapy: Analysis of the adjuvant trials EORTC18952 and EORTC18991 in 2,644 patients

G5 Ulceration of primary melanoma and responsiveness to adjuvant interferon therapy: Analysis of the adjuvant trials EORTC18952 and EORTC18991 in 2,644 patients

Ulceration of primary melanoma and responsiveness to adjuvant interferon therapy: Analysis of the adjuvant trials EORTC18952 and EORTC18991 in 2,644 patients

9007 Background: Ulcerated (Ulc) melanomas have a worse prognosis than non-ulcerated (N-Ulc) melanomas. Ulc and N-Ulc primaries have different stromal characteristics and gene profiles reflecting differences in biology. We analyzed outcome after adjuvant interferon (IFN) therapy in the 2 largest phase III trials (EORTC18952 and 18991) ever conducted in stage IIB-III melanoma patients (pts). Methods: EORTC18952 compared IFNα-2b (10 MIU, sc, qd, 5 days/wk, for 4 wks) followed by either 10MIU,sc, tiw for 12 mts, or 5MIU for 24 mts) with observation in 1,388 stage IIB-III pts (Lancet 2005;366). EORTC18991 evaluated pegylated IFNα-2b (6 μg/Kg, 1×/wk, for 8 wks followed by 3μg/Kg, 1×/wk for up to 5 yrs) versus observation in 1,256 stage III pts (Lancet 2008;372). Using meta-analytical methods, predictive value for Ulc on the value of IFN on relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS) was assessed, overall, and according to stage (IIB, III-N1 or N2=microscopic or macroscopic-nodal disease). Results: Overall, the comparison (PEG-)IFNα-2b versus observation regarding RFS, DMFS, and OS led to a reduction in the hazard ratio (HR) of -16% (SE=5%), -13%(5%), and -8%(5%). Among 2,644 pts randomized, 849 had Ulc primaries, 1,336 N-Ulc primaries, and 459 Ulc unknown. In Ulc group the impact was much greater than in N-Ulc group for RFS (Test For Interaction: p=0.02), DMFS (p<0.001), and OS (p<0.001). The greatest reductions occurred in pts with Ulc and stages IIB/III-N1 In N-Ulc pts reduction was absent. Consistency in the treatment impact was seen in both trials. Conclusions: The post hoc analyses of EORTC1892 and EORTC18991 indicate strongly that pts with an Ulc primary are far more sensitive to IFN than pts with N-Ulc primaries. This hypothesis will now be tested in the EORTC18081 trial, which compares PEG-IFNα-2b versus observation in pts with Ulc primaries ≥ 1mm. [Table: see text] [Table: see text]

Response to interferon therapy affects risk factors for postoperative recurrence of hepatitis C virus‐related hepatocellular carcinoma

Interferon therapy might reduce recurrence after resection of hepatitis C virus-related hepatocellular carcinoma, especially among sustained virologic or biochemical responders. Of 209 patients who underwent curative resection for early-stage hepatitis C virus related hepatocellular carcinoma, 70 patients underwent interferon therapy. A sustained virologic or biochemical response was achieved in 40 patients (SVR/BR group). Thirty no responders and 139 patients who had not received interferon therapy were classified as the NR/non-IFN group. Risk factors for postoperative recurrence in each group were analyzed. The tumor-free survival rates in the SVR/BR group were significantly higher than those in the NR/non-IFN group. By multivariate analysis, the presence of multiple tumors was independently associated with recurrence after resection in both groups, while histologic evidence of cirrhosis was another independent risk factor for postoperative recurrence in the NR/non-IFN group. Newly multicentric carcinogenesis after resection could be suppressed when active hepatitis is controlled by interferon therapy. Patients with single hepatitis C virus related hepatocellular carcinoma detected after successful interferon therapy are good candidates for surgical resection. Adjuvant interferon therapy might be indicated for patients who undergo curative resection for single hepatocellular carcinoma associated with hepatitis C.

A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma.

We conducted a randomized controlled trial of adjuvant interferon therapy in patients with predominantly hepatitis B-related hepatocellular carcinoma (HCC) to investigate whether the prognosis after hepatic resection could be improved. Recurrence is common after hepatic resection for HCC. Interferon possesses antiviral, immunomodulatory, antiproliferative, and antiangiogenic effects and may be an effective form of adjuvant therapy. Since February 1999, patients with no residual disease after hepatic resection for HCC were randomly assigned with stratification by pTNM stage to receive no treatment (control group), interferon alpha-2b 10 MIU/m (IFN-I group) or 30 MIU/m (IFN-II group) thrice weekly for 16 weeks. Enrollment to the IFN-II group was terminated from January 2000 because adverse effects resulted in treatment discontinuation in the first 6 patients. By June 2002, 40 patients each had been enrolled into the control group and IFN-I group. The baseline clinical, laboratory, and tumor characteristics of both groups were comparable. The 1- and 5-year survival rates were 85% and 61%, respectively, for the control group and 97% and 79%, respectively, for the IFN-I group (P = 0.137). After adjusting for the confounding prognostic factors in a Cox model, the relative risk of death for interferon treatment was 0.42 (95% CI, 0.17-1.05; P = 0.063). Exploratory subset analysis showed that adjuvant interferon had no survival benefit for pTNM stage I/II tumor (5-year survival 90% in both groups; P = 0.917) but prevented early recurrence and improved the 5-year survival of patients with stage III/IVA tumor from 24% to 68% (P = 0.038). In a group of patients with predominantly hepatitis B-related HCC, adjuvant interferon therapy showed a trend for survival benefit, primarily in those with pTNM stage III/IVA tumors. Further larger randomized trials stratified for stage are needed.

Autoimmune phenomena as prognostic markers of response to adjuvant interferon therapy for melanoma

Autoimmune phenomena as prognostic markers of response to adjuvant interferon therapy for melanoma

Effect of Interferon-Alpha-2b on Porcine Mesenchymal Stem Cells

Patients undergoing enucleation and adjuvant interferon therapy for giant cell jaw tumors have been observed to exhibit exuberant bone formation in the resultant defects. We hypothesize that interferon promotes bone formation by enhancing mesenchymal stem cell (MSC) differentiation and by stimulating osteoblasts. This is a preliminary study to determine the effects of interferon on porcine mesenchymal stem cells (pMSCs) in culture. Isolated pMSCs were grown under the following conditions: 1) MSCs alone (negative control); 2) MSCs + osteogenic supplements (positive control); and 3) MSCs + interferon (experimental). Cell cultures were evaluated morphologically, by quantitative DNA analysis, and quantitative and qualitative alkaline phosphatase analysis. Cells treated with interferon exhibited a slower but constant proliferation rate, did not clump, and produced more alkaline phosphatase as compared with the negative control. The data indicate that interferon may act to differentiate MSCs into osteoblasts and to stimulate metabolic activity while not increasing the proliferation rate.

Drug-Induced Hepatitis in a Patient with Malignant Melanoma Treated with Interferon Alfa 2b Adjuvantly Who Had Been Administered Gemfibrozil in Therapy

A well-known side effect of chemotherapy, covering a wide range of drugs, is drug-induced hepatitis. We are reporting on a 61-yr-old female patient whose malignant melanoma had been surgically removed, and on whom adjuvant therapy with interferon alfa 2b was initiated. The patient had mild hyperlipidemia, of which she had been aware for several years, but which had gone untreated with medicinal intervention. After the patient was started on interferon alfa therapy, continuously increasing values of triglyceride were measured. Therefore, 3 mo after the introduction of adjuvant therapy, gemfibrozil was prescribed at a dose of 600 mg per day. Within a few days after the patient had been taking this combined therapy, the clinical and laboratory values of drug-induced hepatitis developed. Soon after discontinuance of treatment by both drugs, the signs and symptoms of hepatitis disappeared. Adjuvant interferon therapy was not continued afterward owing to the patient's wish. We do not know if the hepatitis was the side effect to gemfibrozil alone, or the side effect was a result of an interaction between the two drugs. As far as we could find, this is the first case report of possible negative interaction between interferon alfa 2b and gemfibrozil. Our intention in this article is to point out that prescription of any drugs, especially new ones, should be balanced and carefully monitored because of possible side effects.

Potential drug—Drug interaction between interferon alfa-2b and gemfibrozil in a patient with malignant melanoma

Background: In the United States, patients withhigh-risk stage II or III melanoma are often treated with adjuvant interferon (IFN) therapy for 1 year after surgery. Adverse events associated with IFN alfa-2b use are primarily constitutional symptoms. However, hypertriglyceridemia requiring treatment has been reported. Objective: The aim of this report was to describe apotential drug—drug interaction between IFN alfa-2b and gemfibrozil in a patient with malignant melanoma. The possible mechanism of this potential interaction was examined. Methods: This report presents the case of a 43-year-oldmale patient weighing 101 kg with newly diagnosed stage III melanoma of the left arm, with metastasis to the supraclavicular node. The patient presented to the University of California Irvine Medical Center, Orange, California with severe gastrointestinal (GI) symptoms and elevated hepatic enzyme concentrations at week 48 of 104 of adjuvant treatment of malignant melanoma (IFN alfa 11 MU SC TIW in combination with the investigational melanoma vaccine melanoma theraccine 1.25 mL [I mL lysate + 0.25 mL vaccine adjuvant] given SC at weeks 1, 2, 3, 4, 8, 16, 24, 32, 40, and 48 and then every 8 weeks until week 104), and IFN-induced hypertriglyceridemia (gemfibrozil 600 mg PO BID). The patient had no history of cardiovascular or GI disease and was not receiving any concomitant medication. The possible mechanism of this potential IFN alfa-gemfibrozil interaction as related to the cytochrome P450 (CYP) enzyme system was assessed. Results: In this case of a possible drug-drug interactionbetween IFN alfa 11 MU TIW and gemfibrozil 600 mg BID in a patient undergoing treatment for IFN-induced hypertriglyceridemia, the Naranjo Adverse Drug Reactions (ADR) Probability Scale score was 7 (ie, ADR possibly related to treatment). Conclusions: Both IFN and gemfibrozil inhibitthe activity of the hepatic enzymes CYP1A2 and CYP2C19. A possible drug-drug interaction between IFN alfa 11 MU TIW and gemfibrozil 600 mg BID was reported in a patient undergoing treatment for IFN-induced hypertriglyceridemia.

Helping Melanoma Patients Decide Whether to Choose Adjuvant High-Dose Interferon-α2b

High-dose interferon-alpha2b is a U.S. Food and Drug Administration-approved adjuvant treatment for stage III melanoma, and yet, because of its limited efficacy and well-known toxicity, it is not universally accepted by patients and oncologists. In this paper, we evaluate the benefits and risks of adjuvant high-dose interferon-alpha2b and try to provide a framework to help oncologists guide patients trying to decide whether to undergo adjuvant high-dose interferon therapy.

Serum Protein S-100 Predicts Clinical Outcome in Patients with Melanoma Treated with Adjuvant Interferon – Comparison with Tyrosinase RT-PCR

Objective: To study the clinical value of the determination of serum S-100 protein as a single tumor marker or in combination with tyrosinase RT-PCR in patients with melanoma receiving adjuvant interferon. Patients and Methods: Patients were tested for serum S-100 protein luminoimmunometric assay and for blood tyrosinase mRNA (RT-PCR), before starting interferon and every 2–3 months thereafter. Results: One hundred and six patients (stage IIA, 27; IIB, 19; III, 49; and IV, 11) were included in the study. Median follow-up was 51 months (range 2–76). In the univariate analysis, under treatment S-100 ≧0.15 µg/l and a positive RT-PCR correlated with a lower disease-free survival and overall survival (OS). In the multivariate analysis, clinical stage, under therapy positive RT-PCR and S-100 levels ≧0.15 µg/ml, were independent prognostic factors for OS. The hazard ratio for OS was 3.9 (95% CI, 1.67–9.15; p = 0.004) and 2.2 (95% CI, 1.05–4.6; p = 0.016) for S-100 ≧0.15 µg/l and positive RT-PCR, respectively. When both techniques where combined, a positive RT-PCR indicated a poorer clinical outcome only in patients with S-100 <0.15 µg/l. Conclusions: S-100 ≧0.15 µg/l and a positive RT-PCR during adjuvant interferon therapy indicate a high risk of death in resected melanoma patients. S-100 determination has a higher positive predictive value than RT-PCR, while tyrosinase RT-PCR adds prognostic information in patients with S-100 <0.15 µg/l.

High-risk surgically resected pediatric melanoma and adjuvant interferon therapy.

Pediatric patients with high-risk surgically resected melanoma are at risk for relapse, yet little is known about these young patients and how they tolerate high-dose interferon therapy. We reviewed medical records of patients (< or =18 years) with high-risk melanoma referred to the University of Michigan Pediatric Hematology-Oncology service between January 1989 and July 2003. Fourteen patients were identified with high-risk resected melanoma. The median age at diagnosis was 8.5 years. The median time to establish diagnosis was 9 months. Primary lesions were diagnosed as unequivocal melanoma, atypical epithelioid melanocytic proliferations, or atypical Spitz tumor with indeterminate malignant potential. Twelve patients had a positive sentinel lymph node (SLN) biopsy or a palpable regional lymph node and underwent regional lymph node dissection (LND). Two patients with unequivocal melanoma with Breslow depth >4 mm had negative SLN biopsies. Twelve patients received adjuvant high-dose interferon. The following toxicities were observed: constitutional symptoms, gastrointestinal symptoms, depression or neuropsychiatric symptoms, myelosuppression, elevated AST or ALT, hypothyroidism, and hypertension. Grade 3 or 4 toxicities were uncommon with exception of neutropenia, resulting in modification of therapy in one patient. All patients are alive and free of disease at follow-up (median 24.5 months). Invasive melanoma can occur in very young children. Despite early signs of malignancy, there is often a delay in diagnosis. Histologically, diagnosis may be difficult because of overlap with Spitz nevi. Pediatric patients tolerated adjuvant high-dose interferon well and may be less likely than adults to require therapy modification secondary to toxicities.

P-18 Autoimmune disease during adjuvant interferon therapy in patients with malignant melanoma

P-18 Autoimmune disease during adjuvant interferon therapy in patients with malignant melanoma

Cost–Utility of Adjuvant High-Dose Interferon Alpha Therapy in Stage III Cutaneous Melanoma in Quebec

Objective To estimate the cost–utility of adjuvant high-dose interferon in high-risk melanoma patients in Quebec compared to a watchful waiting strategy. Method A Markov model was developed that replicates the findings of the pivotal E1684 trial. It was then used to extrapolate survival over a period of 35 years. Costs of medical resources used during the first year were derived through a detailed analysis of a sample (n = 13) of patients treated in a leading academic hospital. Follow-up costs were assessed through a medical decision algorithm. Utilities were derived from a population-based survey (n = 104) in different locations in Quebec using the time trade-off method. Results The mean incremental cost per quality-adjusted life-year of adjuvant Interferon therapy is equal to CAN$55,090 over a follow-up of 7 years but drops down to CAN$14,003 when extrapolated over 35 years. Conclusions Estimates of the cost-effectiveness of high-dose interferon in melanoma patients show an acceptable cost-effectiveness ratio if long-term survival is taken into account. Estimates are, however, strongly influenced by the observed trial differences in survival, the utility associated to health states, and the discount rate.

A case report of multicentric verrucous carcinoma of the female genital tract

Background Verrucous carcinoma is a variant of squamous cell carcinoma with distinct features including slow locally invasive growth and verrucous appearance. Verrucous carcinoma of the vagina is considered an extremely rare lesion because only 17 cases have been reported in the literature. Case We report a case of vaginal verrucous carcinoma with a second focus in the cervix. The patient was treated with surgery and adjuvant interferon therapy for local recurrence. Human papillomavirus was detected in both vaginal and cervical tumor tissue by immunohistochemistry. Conclusions Diagnosis of verrucous carcinoma may be difficult, particularly if biopsy specimen involves only the surface epithelium. The role of human papillomavirus as an etiologic agent in verrucous carcinoma is still a matter of discussion. Effective management requires surgical resection. The efficiencies of radiotherapy and interferon therapy are discussed.

Ocular complications of adjuvant interferon therapy for malignant melanoma: a review

In dermatology, interferon Alfa 2 is used in adjuvant therapy of melanoma (stage IIa/b) as well as in treatment of cutaneous lymphoma or melanoma (stage III or higher). In the past 2 years, several case reports have described interferon-induced ocular side effects, including sudden loss of vision and ischemic retinopathy. We wondered if incidence and prognosis of ocular complications were elevated in patients receiving an adjuvant treatment of melanoma with interferons. We analyzed 1334 reports of adverse effects of interferons, which had been spontaneously reported in Germany since 1990. 8.4% of all reported adverse effects of interferons were ocular. More than the half of these patients developed significant visual loss including retinal ischemia. These data underscore the importance to inform patients concerning ocular adverse effects and emphasize the need to monitor the retina during adjuvant interferon therapy.

Cost-effectiveness of adjuvant interferon therapy after surgical resection of Hepatitis C-related hepatocellular carcinoma.

To evaluate cost-effectiveness of adjuvant interferon therapy used with surgical resection of hepatitis C-related primary hepatocellular carcinoma. We constructed a Markov model that simulated adjuvant interferon therapy after resection of hepatitis C-related hepatocellular carcinoma, and evaluated life expectancy, costs, and cancer recurrence. The reference case is a 60-year-old man with hepatitis C-related compensated cirrhosis. At the baseline, adjuvant interferon therapy yielded 6.1 life years with a cost of dollars 77000, and an incremental cost-effectiveness ratios of dollars 15700/life year compared with no interferon therapy. The proportion of patients who experienced recurrence of hepatocellular carcinoma until death was reduced from 87.6% to 62.9% using adjuvant interferon therapy. The incidence of recurrent hepatocellular carcinoma after interferon influenced the cost-effectiveness of adjuvant interferon therapy. A threshold analysis showed that adjuvant interferon therapy was not cost-effective (ICER = dollars 27000/year) if the annual incidence of recurrent hepatocellular carcinoma after interferon is 16% (baseline 8.9%). The proportions of patients with recurrent hepatocellular carcinoma were 74.4% and 86.9% at the annual recurrence rates after interferon of 16% and 35%, respectively. Adjuvant interferon therapy after surgical resection of primary hepatitis C-related hepatocellular carcinoma improves life expectancy through suppression of recurrent cancer with acceptable cost-effectiveness.

Modelling the cost-effectiveness of sentinel lymph node mapping and adjuvant interferon treatment for stage II melanoma.

Clinical studies have demonstrated that high dose adjuvant interferon therapy improves disease-free and overall survival among high risk (stage IIb and III) melanoma patients. Sentinel lymph node mapping (SLM) has been shown to accurately detect micrometastasis and may be used to identify higher risk stage II patients, who might benefit most from adjuvant interferon therapy. We modelled the cost-effectiveness of first testing with SLM and then treating with adjuvant interferon (IFN) therapy for stage II melanoma. We used a decision analytical model to compare four strategies for stage II patients after surgical excision of their melanoma: (1) treat all with low dose IFN; (2) test first with SLM and then treat only those with positive micrometastasis with high dose IFN; (3) test first with SLM and treat positives with high dose IFN and negatives with low dose IFN (test and treat appropriately); and (4) surgery only. Treatment, toxicity, follow-up and relapse costs were included over a 5 year time period. The primary outcome was cost per quality-adjusted relapse-free life year saved. Our analysis shows that, compared with the current surgery-only strategy, all three treatment strategies provide incremental benefits. The test and treat appropriately strategy is the most effective, with an incremental improvement of 0.64 quality-adjusted life-years (QALY). The cost-effectiveness of test and treat some with high dose IFN compared with the surgery-only strategy is $18,700/QALY. The test and treat appropriately strategy is also cost-effective compared with test and treat some at $31,100/QALY. In conclusion appropriate dosing of IFN therapy based on the results of SLM is a cost-effective strategy for stage II melanoma patients.

Tyrosinase mRNA in blood of patients with melanoma treated with adjuvant interferon.

To evaluate the clinical significance of the detection of circulating melanoma cells in patients treated with adjuvant interferon and to determine their potential value as a marker of interferon response. We prospectively analyzed 616 peripheral-blood samples from 120 melanoma patients with stage IIA (n = 33), IIB (n = 22), III (n = 50), or IV (surgically resected) (n = 15) disease receiving adjuvant interferon alfa-2b therapy. Tyrosinase mRNA was assayed by reverse transcriptase polymerase chain reaction (RT-PCR) as a marker of circulating melanoma cells before the start of interferon and every 2 to 3 months thereafter. With a median follow-up time of 32.3 months (range, 7.1 to 77.5 months), 47 patients (39.8%) relapsed and 31 (26%) died. During adjuvant interferon treatment, 76 patients (64%) had undetected circulating melanoma cells and 44 patients (36%) had a positive RT-PCR result in at least one sample. Actuarial 5-year disease-free survival was 62% in patients with persistently negative RT-PCR during interferon treatment and 38% for patients with positive RT-PCR during interferon (P =.02). Actuarial 5-year overall survival was 75% and 50%, respectively (P =.03). Patients with melanoma and tyrosinase mRNA detected in the blood during adjuvant interferon therapy had a worse prognosis compared with patients with undetected tyrosinase mRNA during treatment. Further investigation into the detection of circulating melanoma cells as a surrogate marker of response to adjuvant interferon therapy is warranted.

Determination of Potential Adjuvant Systemic Therapy Benefits for Patients With Resected Cutaneous Melanomas

Objective To facilitate both better physician understanding of prognostic information (baseline and with adjuvant interferon) for individual patients who present with resectable melanomas and more informed patient decisions about whether they should receive adjuvant high-dose interferon therapy after resection of primary melanomas. Patients and Methods Baseline survival estimates were derived from a surgical database composed of 17,600 patients with complete clinical, pathologic, and follow-up data. Potential survival benefits ascribed to adjuvant interferon were obtained from results of a meta-analysis of Eastern Cooperative Oncology Group studies, which provided evidence for a uniform relative benefit of high-dose interferon across different baseline risk groups. A mathematical formula was then applied to these data to allow for individual prognostic information. Results The 5-year survival benefits in patients who received high-dose interferon after surgery, using the assumptions of the provided prognoses and interferon survival improvements, ranged up to 13%. Conclusions These data should allow for a better understanding of baseline prognosis in individual patients and a better understanding of the potential benefits of adjuvant interferon. They should also help patients make more informed decisions regarding their treatment options. To facilitate both better physician understanding of prognostic information (baseline and with adjuvant interferon) for individual patients who present with resectable melanomas and more informed patient decisions about whether they should receive adjuvant high-dose interferon therapy after resection of primary melanomas. Baseline survival estimates were derived from a surgical database composed of 17,600 patients with complete clinical, pathologic, and follow-up data. Potential survival benefits ascribed to adjuvant interferon were obtained from results of a meta-analysis of Eastern Cooperative Oncology Group studies, which provided evidence for a uniform relative benefit of high-dose interferon across different baseline risk groups. A mathematical formula was then applied to these data to allow for individual prognostic information. The 5-year survival benefits in patients who received high-dose interferon after surgery, using the assumptions of the provided prognoses and interferon survival improvements, ranged up to 13%. These data should allow for a better understanding of baseline prognosis in individual patients and a better understanding of the potential benefits of adjuvant interferon. They should also help patients make more informed decisions regarding their treatment options.

Determination of Potential Adjuvant Systemic Therapy Benefits for Patients With Resected Cutaneous Melanomas

To facilitate both better physician understanding of prognostic information (baseline and with adjuvant interferon) for individual patients who present with resectable melanomas and more informed patient decisions about whether they should receive adjuvant high-dose interferon therapy after resection of primary melanomas. Baseline survival estimates were derived from a surgical database composed of 17,600 patients with complete clinical, pathologic, and follow-up data. Potential survival benefits ascribed to adjuvant interferon were obtained from results of a meta-analysis of Eastern Cooperative Oncology Group studies, which provided evidence for a uniform relative benefit of high-dose interferon across different baseline risk groups. A mathematical formula was then applied to these data to allow for individual prognostic information. The 5-year survival benefits in patients who received high-dose interferon after surgery, using the assumptions of the provided prognoses and interferon survival improvements, ranged up to 13%. These data should allow for a better understanding of baseline prognosis in individual patients and a better understanding of the potential benefits of adjuvant interferon. They should also help patients make more informed decisions regarding their treatment options.