Adjuvant Interferon-alpha Research Articles

Tumour regression predicts better response to interferon therapy in melanoma patients: a retrospective single centre study.

We hypothesise that regression may have an impact on the effectiveness of adjuvant IFN therapy, based on its role in the host immune response. Our purpose is to investigate regression and ulceration as prognostic factors in case of interferon-alpha (IFN)-treated melanoma patients. We followed 357 IFN-treated melanoma patients retrospectively, investigating progression-free survival (PFS) and overall survival (OS) depending on the presence of ulceration and regression. A Kaplan-Meier analysis was performed, and we used a Cox regression analysis to relate risk factors. The survival function of the Cox regression was used to measure the effect of regression and ulceration on PFS and OS depending on the Breslow thickness (T1-T4) of the primary tumour. Regression was significantly positively related to PFS ( P = 0.0018, HR = 0.352) and OS ( P = 0.0112, HR = 0.380), while ulceration showed a negative effect (PFS: P = 0.0001, HR = 2.629; OS: P = 0.0003, HR = 2.388). They influence survival independently. The most favourable outcome was measured in the regressed/non-ulcerated group, whereas the worse was in the non-regressed/ulcerated one. Of risk factors, Breslow thickness is the most significant predictor. The efficacy of regression is regardless of Breslow thickness, though the more favourable the impact of regression was in the thicker primary lesions. Our results indicate that regression is associated with a more favourable outcome for IFN-treated melanoma patients, whereas ulceration shows an inverse relation. Further studies are needed to analyse the survival benefit of regression in relation to innovative immune checkpoint inhibitors.

Adjuvant Topical Interferon Alpha 2b for the Treatment of Monkeypox Ocular Manifestations.

The aim of this study was to report a case of ocular Mpox that responded favorably to treatment with topical interferon and oral doxycycline. This is a case report of a previously healthy 24-year-old woman who developed a pustular rash, headache, fever, arthralgia, sore throat, and asthenia 3 weeks before attending to our clinic. Her main complaint at the moment of the visit was pain, photophobia, foreign body sensation, blurred vision, red eye, and discharge on the left eye. The slit-lamp examination of the left eye showed severe conjunctival hyperemia associated with tarsal follicles, 360 degrees ciliary injection, diffuse corneal epithelial edema with white linear epithelial infiltrates, pigmented and nonpigmented keratic precipitates, and two 1-mm peripheral corneal ulcers with white infiltrates, associated with positive fluorescein staining. Anterior chamber cellularity and flare were mildly present. Mpox with ocular manifestations diagnosis was confirmed by real-time quantitative reverse transcription polymerase chain reaction assay (qRT-PCR) testing; samples were taken from corneal, conjunctival, and nasopharynx swab as well as a skin scab. Topical interferon alpha 2b 1 MIU/mL every 6 hours for 1 month and oral doxycycline 100 mg BID were administered along with other medications with consequent decrease of inflammation and malaise symptoms 1 week later, associated with uncorrected visual acuity improvement. Alternative and efficacious treatment options for Mpox ocular manifestations are needed to prevent further disease progression and sequelae in countries with no access to the gold-standard therapy. Topical interferon alpha 2b and oral doxycycline have shown adequate response as shown with this patient.

Immunotherapy for metastatic melanoma—from little benefit to first-line treatment

SummaryAt the turn of the past century, unresectable metastatic melanoma was primarily treated with different chemotherapeutic agents, such as dacarbazine, with only poor efficacy. Immunotherapeutic agents, such as interleukin‑2 or adjuvant interferon alpha, were used with modest results but frequent side effects. In the last 10 years, modern immunotherapy using checkpoint inhibition has dramatically changed the treatment landscape of metastatic melanoma and is now considered the first-line treatment for stage IV melanoma. Consequently, median overall survival has increased from 9.1 months with dacarbazine to up to 72.1 months using the current gold standard ipilimumab + nivolumab first-line. In 2023, in Europe, the anti-PD1 antibodies nivolumab and pembrolizumab are licensed in the adjuvant and metastatic setting and the combination therapies ipilimumab + nivolumab and relatlimab + nivolumab are approved in the metastatic setting. Nevertheless, despite tremendous progress in the last two decades, at least 50% of our patients with stage IV melanoma still die. Currently, research focuses on combining checkpoint inhibition with other drugs such as cancer vaccines, BRAF/MEK inhibition, other tyrosine kinase inhibitors or histone deacetylase inhibitors.

Association of prior interferon-alpha treatment with the efficacy of adjuvant pembrolizumab in resected melanoma.

e22100 Background: Adjuvant pembrolizumab or interferon-alpha has been found to prolong recurrence-free survival as adjuvant therapy for resected melanoma. Several studies have shown that interferon-alpha could modulate immune responses to melanoma. In this study, we provided clear evidence that prior treatment with interferon-alpha significantly enhanced the efficacy of adjuvant pembrolizumab for resected melanoma. Methods: 57 patients with acral or cutaneous melanoma (stage IB or II) were enrolled. After resection of the primary tumors, 25 patients received high-dose interferon-alpha as adjuvant therapy and 32 patients received observation. The patients eventually progressed to stage III or IV, with nodal, in-transit, or resectable distant recurrence. Then the patients underwent complete resection for the recurrent tumors. Next, all the patients were given 100 mg of pembrolizumab every 3 weeks. We compared progression-free survival (the time between the date of starting anti-PD-1 and the date of recurrence after anti-PD-1) between the subgroup receiving prior adjuvant interferon-alpha treatment (IFN-pembrolizumab) and the subgroup receiving observation (pembrolizumab). Results: In the pembrolizumab group, 9.4% (3 of 32) had a recurrence within two months and 38% (12 of 32) had disease progression within four months. Whereas, no patients had a recurrence within two months and the proportion of patients with less than four months PFS was 16% (4 of 25) in the IFN-pembrolizumab group. Furthermore, 44% (11 of 25) had a relapse until the date of last follow-up in the IFN-pembrolizumab group. But 56% (18 of 32) had a recurrence in the pembrolizumab group. The Kaplan-Meier curve showed that PFS was significantly improved in the IFN-pembrolizumab group as compared with the pembrolizumab group (mPFS 34.6 weeks vs. 18 weeks, HR = 0.47, 95% CI 0.23-0.99; p value = 0.0392). For stage III melanoma, mPFS was not reached in the IFN-pembrolizumab group, demonstrating increased benefit for patients with early stage. Altogether, these data suggested that prior interferon-alpha treatment could prolong PFS for adjuvant pembrolizumab. Conclusions: In this study, we for the first time demonstrated that prior treatment with adjuvant IFN-alpha exhibited significant improvement for adjuvant pembrolizumab. Meanwhile, further investigation is required to dissect how IFN-alpha enhanced the efficacy of PD-1 blockade.

Abstract 3971: MTA-mediated inhibition of human T cells: Mechanism and MTAP overexpression as putative overcoming strategy

Abstract Metabolic changes of malignant cells lead to the secretion of tumor metabolites which contribute to the shaping of a favorable milieu for tumor immune escape facilitating cancer development and resistance to anti-tumor immunotherapy. Recently, disrupted methylthioadenosine metabolism drew interest as further putative immunoinhibitory metabolic dysregulation. A broad spectrum of tumor entities was reported to lack methylthioadenosine phosphorylase (MTAP) expression leading to elevated levels of its substrate 5’-deoxy-5’-methylthioadenosine (MTA). MTAP deficiency is reported to correlate with worse response to adjuvant interferon-alpha therapy and a higher risk for metastatic disease in malignant melanoma providing evidence for immunobiological relevance. We therefore examined the effect of the tumor metabolite MTA on human T cell responses. We could show that MTA has a strong inhibitory impact on human T cell function regarding proliferation, viability, activation, differentiation, tumor antigen-specific expansion and cytotoxicity. We therefore aimed to overexpress MTAP in human T cells by retroviral transduction as a putative strategy to overcome MTA-mediated inhibition of T cells. In addition, we investigated the effect of MTA on T cell metabolism and maturation of human monocyte derived mDC. We successfully generated stable MTAP-overexpressing primary human T cells. First studies were performed to examine the resistance to MTA after equipping the T cells with higher levels of its metabolizing enzyme MTAP. MTAPhigh T cells revealed less sensitivity against inhibitory effects of MTA on proliferation, viability or cytotoxicity compared to mock transduced controls suggesting a promising approach to strengthen the performance of T cells facing the MTA-rich milieu of MTAP-deficient tumors. Mechanistically, we found MTA to interfere with several signaling pathways. Of most importance, MTA impaired Akt phosphorylation as well as intracellular protein methylation, both crucial processes for proper T cell function. In addition, we studied the combined effect of MTA and PRMT5 inhibition on T cells. Several metabolic studies focusing on glycolysis and fatty acid metabolism could confirm our findings that MTA keeps T cells in a rather inactive, naïve state. Finally, we found MTA to interfere with DC maturation and their potential to induce cytokine secretion of T cells. Our data emphasizes the crucial role of tumor metabolites such as MTA in the tumor milieu for tumor immune escape. Additionally, the identification of potential molecular mechanisms of MTA-induced immunosuppression offer the opportunity to pharmacologically tackle MTA-mediated immunoinhibition and will help to develop more effective immune-based therapies against MTAP-deficient tumors. Citation Format: Carolin D. Strobl, Frederik Henrich, Katrin Singer, Katrin Peter, Marina Kreutz, Anita Kremer, Andreas Mackensen, Michael Aigner. MTA-mediated inhibition of human T cells: Mechanism and MTAP overexpression as putative overcoming strategy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3971. doi:10.1158/1538-7445.AM2017-3971

What are the benefits and harms of the adjuvant treatment interferon alpha in people with stage II or III cutaneous melanoma?

What are the benefits and harms of the adjuvant treatment interferon alpha in people with stage II or III cutaneous melanoma?

Evaluation of serum osteopontin level and gene polymorphism as biomarkers: analyses from the Nordic Adjuvant Interferon alpha Melanoma trial.

Malignant melanoma is highly aggressive cancer with poor prognosis and few therapeutic options. Interferon alpha (IFN-α) has been tested as adjuvant immunotherapy in high-risk melanoma patients in a number of studies, but its beneficial role is controversial. Although IFN-α treatment can prolong relapse-free survival, the effect on overall survival is not significant. However, a small subset of patients benefits from the treatment, signifying the need for biomarkers able to identify a responding subgroup. Here we evaluated whether serum osteopontin (OPN) could function as a biomarker identifying patients with poor prognosis that might benefit from IFN-α. The choice of osteopontin was based on the knowledge about the dual role of this protein in cancer and immune response, an apparent association between OPN and IFN signaling and a prognostic value of OPN in multiple other tumor types. Serum samples from 275 high-risk melanoma patients enrolled in the Nordic Adjuvant IFN Melanoma trial were analyzed for circulating OPN concentrations and OPN promoter polymorphisms in position -443. The potential relation between serum OPN levels, the genotypes and survival in non-treated patients and patients receiving adjuvant IFN-α was investigated. Although slightly better survival was observed in the treated patients that had high levels of OPN, the difference was not statistically significant. In conclusion, serum OPN (its level or the genotype) cannot distinguish melanoma patients with poor prognosis, or patients that might benefit from adjuvant treatment with IFN-α.

Interferon alpha for the adjuvant treatment of cutaneous melanoma.

Interferon alpha is the only agent approved for the postoperative adjuvant treatment of high-risk cutaneous melanoma. However, the survival advantage associated with this treatment is unclear, especially in terms of overall survival. Thus, adjuvant interferon is not universally considered a gold standard treatment by all oncologists. To assess the disease-free survival and overall survival effects ofinterferon alpha as adjuvant treatment for people with high-risk cutaneous melanoma. We searched the following databases up to August 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, issue 8), MEDLINE (from 2005), EMBASE (from 2010), AMED (from 1985), and LILACS (from 1982). We also searched trials databases in 2011, and proceedings of the ASCO annual meeting from 2000 to 2011. We checked the reference lists of selected articles for further references to relevant trials. We included only randomised controlled trials (RCTs) comparing interferon alpha to observation (or any other treatment) for the postoperative (adjuvant) treatment of patients with high-risk skin melanoma, that is, people with regional lymph node metastasis (American Joint Committee on Cancer (AJCC) TNM (tumour, lymph node, metastasis) stage III) undergoing radical lymph node dissection, or people without nodal disease but with primary tumour thickness greater than 1 mm (AJCC TNM stage II). Two authors extracted data, and a third author independently verified the extracted data. The main outcome measure was the hazard ratio (HR), which is the ratio of the risk of the event occurring in the treatment arm (adjuvant interferon) compared to the control arm (no adjuvant interferon). The survival data were either entered directly into Review Manager (RevMan) or extrapolated from Kaplan-Meier plots and then entered into RevMan. Based on the presence of between-study heterogeneity, we applied a fixed-effect or random-effects model for calculating the pooled estimates of treatment efficacy. Eighteen RCTs enrolling a total of 10,499 participants were eligible for the review. The results from 17 of 18 of these RCTs, published between 1995 and 2011, were suitable for meta-analysis and allowed us to quantify the therapeutic efficacy of interferon in terms of disease-free survival (17 trials) and overall survival (15 trials). Adjuvant interferon was associated with significantly improved disease-free survival (HR (hazard ratio) = 0.83; 95% CI (confidence interval) 0.78 to 0.87, P value < 0.00001) and overall survival (HR = 0.91; 95% CI 0.85 to 0.97; P value = 0.003). We detected no significant between-study heterogeneity (disease-free survival: I² statistic = 16%, Q-test P value = 0.27; overall survival: I² statistic = 6%; Q-test P value = 0.38).Considering that the 5-year overall survival rate for TNM stage II-III cutaneous melanoma is 60%, the number needed to treat (NNT) is 35 participants (95% CI = 21 to 108 participants) in order to prevent 1 death. The results of subgroup analysis failed to answer the question of whether some treatment features (i.e. dosage, duration) might have an impact on interferon efficacy or whether some participant subgroups (i.e. with or without lymph node positivity) might benefit differently from interferon adjuvant treatment.Grade 3 and 4 toxicity was observed in a minority of participants: In some trials, no-one had fever or fatigue of Grade 3 severity, but in other trials, up to 8% had fever and up to 23% had fatigue of Grade 3 severity. Less than 1% of participants had fever and fatigue of Grade 4 severity. Although it impaired quality of life, toxicity disappeared after treatment discontinuation. The results of this meta-analysis support the therapeutic efficacy of adjuvant interferon alpha for the treatment of people with high-risk (AJCC TNM stage II-III) cutaneous melanoma in terms of both disease-free survival and, though to a lower extent, overall survival. Interferon is also valid as a reference treatment in RCTs investigating new therapeutic agents for the adjuvant treatment of this participant population. Further investigation is required to select people who are most likely to benefit from this treatment.

Development of a miR-26 Companion Diagnostic Test for Adjuvant Interferon-alpha Therapy in Hepatocellular Carcinoma

Background & Aims: Adjuvant therapies for hepatocellular carcinoma (HCC) such as interferon-alpha are effective only in a subset of patients. Previously we found that HCC patients with low level of miR-26 have survival benefits from interferon-alpha. The purpose of this study is to develop a standardized miR-26 diagnostic test (referred as MIR26-DX) to assist identification of candidate HCC patients for adjuvant interferon-alpha therapy.Methods: We developed a multiplex reverse-transcription quantitative polymerase-chain-reaction assay to determine the levels of two HCC-related miR-26 transcripts along with six small RNA reference transcripts. We evaluated archived paraffin-embedded tissues from three cohorts of HCC patients (n=248) who underwent radical resection at three different clinical centers. Fifty-two percent of them underwent adjuvant interferon-alpha therapy. We used Cox-Mantel log-rank test to evaluate patient survival.Results: We found that the multiplexing assay was stable and reproducible regardless of differences in sample preparations and operators. We developed a matrix template and a scoring algorithm based on a training cohort (n=129) to assign HCC patients, and then applied the template in two test cohorts (n=119). The proportions of HCC patients assigned as low miR-26 by this algorithm were 68, 4, and 63 percent in the training cohort and two test cohorts, respectively. Consistently, HCC with low miR-26 had a favorable response to interferon-alpha with improved median overall survival (≥3year).Conclusions: MIR26-DX is a simple and reliable companion diagnostic test to select HCC patients for adjuvant interferon-alpha therapy.

Adjuvant Interferon Therapy for Patients at High Risk for Recurrent Melanoma: An Updated Systematic Review and Practice Guideline

After complete resection of melanoma, some patients remain at high risk for recurrence. The efficacy of adjuvant systemic therapy has been inconsistent in randomised trials and remains controversial. An updated systematic review was conducted to identify new evidence on the role of adjuvant interferon therapy in patients with high-risk resected primary melanoma. Outcomes of interest included overall survival, disease-free survival (DFS), adverse effects and quality of life. MEDLINE, EMBASE, Cochrane Library and the proceedings of the American Society of Clinical Oncology were systematically searched to identify new randomised controlled trials, systematic reviews or meta-analyses. An updated meta-analysis of trials comparing high-dose interferon alpha with observation alone was conducted. The new data are presented in this review. Seven randomised controlled trials met the inclusion criteria: six trials of interferon alone and two trials of interferon plus chemotherapy. Two meta-analyses of adjuvant interferon alpha were also identified. Overall survival was not significantly different between adjuvant high-dose interferon and observation alone (hazard ratio 0.93; 95% confidence interval 0.78–1.12; P = 0.45). A meta-analysis of DFS showed a significant benefit for high-dose interferon over control (hazard ratio 0.77; 95% confidence interval 0.65–0.92; P = 0.004). One trial reported a significant DFS benefit for pegylated interferon over observation alone. Our updated literature review indicates that adjuvant interferon therapy does not confer a significant long-term overall survival benefit in patients with high-risk resected primary melanoma; however, a significant DFS benefit for high-dose interferon or pegylated interferon treatment has been shown. An revised practice guideline was developed based on the systematic review.

Wide surgical excision combined with low-dose adjuvant interferon-alpha 2b for the treatment of invasive cutaneous malignant melanoma: 32 case reports

Objective To retrospectively analyze the therapeutic effect of wide surgical excision combined with low-dose adjuvant interferon-alpha 2b on cutaneous malignant melanoma.Methods A total of 32 patients with cutaneous malignant melanoma received wide surgical excision after preoperative examination and staging.The excisions were performed with a margin measuring 1-2 cm from the visible lesions or biopsy scars.Surgical modalities included direct suture after excision(4 patients),dactylolysis or toe amputation(6 patients),free skin grafting(15 patients),random skin flap transfer(3 patients)and pedicle skin flap transfer(4 patients).Lymph nodes were selectively dissected in 9 patients with regional transfer of lymph nodes,and inguinal lymph nodes were cleared away in 2 patients.One week after the operation,patients received adjuvant therapy with subcutaneous injection of interferon-alpha 2b(3 million IU,thrice per week)for one to three years.Results Preoperative tumor staging revealed 21 cases of cutaneous malignant melanoma at stage Ⅱ,and 11 cases at stage Ⅲ.The excisions healed by the first stage in all the patients.Up to June 2011,2 patients had been lost to follow up,5 patients with stage Ⅲ melanoma had died.Survival was observed in all of the 4 patients receiving 1-year follow up,12 of 13 patients receiving 1-3 year follow up,5 of 7 patients receiving 3-5 year follow up,and 4 of 6 receiving 5-year follow up.Of the 25 surviving patients,regional lymph node metastasis was observed in 8 patients,which developed within 2 years after the operation in 2 patients.The adjuvant therapy with interferon-alpha 2b lasted 3 years in 8 patients,and more than 1 year in 11 patients.Side effects were mild.Conclusion Wide surgical excision plus low-dose interferon-alpha 2b is effective for the treatment of stage Ⅱ and Ⅲ cutaneous malignant melanoma with lower local recurrence and higher survival rate. Key words: Melanoma; Surgical procedures, operative; Interferon alfa-2b

Final results from an EORTC (GU Group)/NCRI randomized phase III trial of adjuvant interleukin-2, interferon alpha, and 5-fluorouracil in patients with a high risk of relapse after nephrectomy for renal cell carcinoma (RCC).

4505 Background: Despite an apparently curative resection, 30% of patients with RCC will develop metastases. Histological risk factors can predict those at highest risk. The role of adjuvant treatm...

Pericardial effusion and tamponade following interferon alpha treatment for locally advanced melanoma

Regional Metastatic Melanoma has a relatively high mortality rate. Adjuvant interferon-alpha (IFN-α) has been shown to improve disease-free survival, post-resection. Cardiotoxicity associated with IFN-α use has been described previously in the literature, but here we describe the first case of pericardial effusion with cardiac tamponade secondary to IFN-α 2b treatment of melanoma. Clinicians should be aware of this potentially lethal complication and the possible acuity of its onset.

Moyamoya in a Child Treated With Interferon for Recurrent Osteosarcoma

Moyamoya is a cerebral vasculopathy of unknown etiology rarely described as a late effect after the treatment of childhood cancer. We describe a 12-year-old female who developed moyamoya after the completion of systemic chemotherapy, surgery, and adjuvant interferon alpha for osteosarcoma with pulmonary metastases. Given the importance of characterizing late effects after the treatment of childhood cancer, the potential role of interferon alpha in the development of moyamoya is discussed.

Induction of IP-10/CXCL10 secretion as an immunomodulatory effect of low-dose adjuvant interferon-alpha during treatment of melanoma☆

This study investigated the immunomodulatory effects of low-dose interferon-alpha (IFN-alpha) in a cohort of 21 stage II or III melanoma patients treated in an adjuvant setting. Serial assessments in peripheral blood were performed at baseline and at regular intervals. Depletion of CD3+CD4+ T cells was predominant within the "central memory" and "memory" subsets. The impact of IFN-alpha was more marked at the level of all CD3+CD8+ T-cell subsets that showed a sustained and significant decrease. Both myeloid and plasmacytoid dendritic cell (DC) subsets were depleted, but the MDC/PDC ratio tended to increase 12 months after treatment. Also, CD14+CD16+ monocytes showed a significant increase of both MHC class I and the CD86 costimulatory molecule. IP-10/CXCL10 plasma levels significantly increased already at 3 months of therapy and remained at significantly high levels during the study period. The dramatic increase of IP-10/CXCL10 inversely correlated with a significant decrease of the CXCR3+CD8+ T lymphocytes. Low-dose IFN-alpha therapy can significantly affect phenotypic and functional properties of blood circulating lymphocytes and antigen-presenting cells, and production of IP-10/CXCL10, that appear to be important for the orchestration of an effective immune response during adjuvant IFN-alpha therapy for melanoma.

Efficacy of Adjuvant Interferon-alpha Therapy Following Curative Resection in Renal Cell Carcinoma: Before the Molecular Targeting Therapy Era

Although present treatment programs for renal cell carcinoma (RCC) typically involve molecular-targeting drugs, interferon-alpha (IFN-alpha) remains an important therapeutic drug for this cancer. We evaluated the effect of adjuvant therapy in 508 patients with RCC following curative surgery. Patients were classified into one of the two categories based on the duration and the total dose of IFN-alpha treatment. Median follow-up time was 65.5 months. Overall survival rates at 5, 10, 15 and 20 years were 88.8%, 80.5%, 69.6% and 54.1%, respectively. Cause-specific survival rates at 5, 10, 15 and 20 years were 95.0%, 89.1%, 83.0% and 83.0%, respectively. Cox's proportional hazard model revealed that C-reactive protein, T classification, histological grade and age were significantly independent factors indicative of a poor prognosis. Our examination of the 253 patients diagnosed as pT1-2N0M0 who underwent adjuvant IFN-alpha therapy following surgery found that the therapy was not significantly associated with either cause-specific or disease-free survival. With regard to effects of duration of therapy and total dose of IFN-alpha, patients with a total IFN-alpha exposure of > or = 180 x 10(6) international units (IU) had a better prognosis than those exposed to <180 x 10(6) IU. Adjuvant therapy using large doses of IFN-alpha may improve the prognosis of patients with RCC following curative resection, and the new possibility of IFN-alpha therapy merits further investigation.

Interdisciplinary management recommendations for toxicity associated with interferon‐alfa therapy

Adjuvant interferon-alpha (IFN-alpha) therapy in patients with melanoma has been established as standard therapy since more than 10 years.During IFN-alpha therapy, flu-like symptoms, gastrointestinal disorders, arthralgias and neuropsychiatric symptoms are the most common side effects. The management and prophylaxis of these side effects have been improved by a more detailed understanding of pathophysiologic mechanisms and increased clinical experience. New insights in the relevance of detection of autoantibodies and development of autoimmunity have influenced the clinical pathway substantially. This review covers the pathomechanisms, incidence and optimized therapy of IFN-alpha-associated side effects.

Preliminary results from a randomized phase III trial of adjuvant interleukin-2, interferon alpha and 5-fluorouracil in patients with a high risk of relapse after nephrectomy for renal cell carcinoma (RCC)

5040 Background: Despite an apparently curative resection, 30% of patients with RCC will develop metastases. Histological risk factors can predict those at highest risk. The role of adjuvant treatm...

Adjuvant high‐dose interferon for cutaneous melanoma is most beneficial for patients with early stage III disease

Evidence from randomized trials in the pre-sentinel lymph node biopsy era indicate that adjuvant treatment with high-dose interferon-alpha (IFN) increases recurrence-free survival (RFS) in patients with high-risk melanoma. However, to the authors' knowledge, the role of this treatment in selected patients with early stage III disease has not been well studied. The clinical and pathologic characteristics of 486 patients undergoing surgical treatment for stage III melanoma were evaluated and the authors compared outcomes for those given adjuvant treatment with IFN with those patients who had surgery alone. A particular focus was on the effect of IFN therapy on RFS and overall survival (OS) among those patients with stage IIIA disease. The median follow-up for the entire cohort was 5.2 years; the 5-year RFS and OS rates for the entire group were 41% and 53%, respectively. Adjuvant IFN was given to 141 patients (29%). On multivariate analysis, IFN was found to be the only independent predictor for RFS in patients with stage IIIA disease (hazards ratio of 0.4; 95% confidence interval, 0.2-0.9 [P = .02]). IFN was not found to be associated with increased RFS in patients with more advanced lymph node disease (stage IIIB and stage IIIC). IFN appeared to have no effect on OS in any patient with stage III disease. Adjuvant treatment with IFN improves RFS in melanoma patients with early stage III disease. The results of the current study should help guide management when considering adjuvant treatment for these patients.

Evidence-based and interdisciplinary consensus-based German guidelines: systemic medical treatment of melanoma in the adjuvant and palliative setting

Systemic medical treatment of melanoma is administered in the adjuvant and palliative setting. Adjuvant therapy may be considered in patients with primary melanoma with more than 1.5 mm tumor thickness and with regional node metastasis. Presently no indication for systemic adjuvant chemotherapy or for adjuvant therapy with nonspecific immune-stimulatory agents outside controlled studies is seen. Interferon-alpha is the first substance in the adjuvant therapy of melanoma, which has shown to present a significant advantage to the patients in some prospective randomized studies. Good arguments for using adjuvant interferon-alpha therapy in high-risk melanoma patients exist. Both high-dose and low-dose interferon-alpha show promise. The major indications for systemic chemotherapy and chemoimmunotherapy are inoperable recurrent tumors, inoperable regional metastases and distant metastases (stage IV). As treatment in such situations is primarily palliative, the effect of any regimen on the quality of life must be carefully weighed. As a first line treatment, single agent therapy is recommended, as polychemotherapy or biochemotherapy did not show significant advantages for prolongation of survival; hence they are more toxic. An urgent need for development of new treatment modalities is necessary and general principles of experimental immunotherapy are outlined.