Chemical peelings for the treatment of actinic keratosis: a systematic review and meta-analysis.

BACKGROUND: Actinic keratosis (AK) is a common precancerous lesion of the skin that may be treated with chemical peelings. Despite their long-standing usage and clinical experience, no evidence-based recommendation regarding the efficacy and safety of chemical peelings for AK exists. OBJECTIVES: To systematically review and synthesize the current knowledge on chemically exfoliative peelings as interventions for AK. METHODS: We performed a systematic literature research in Medline, Embase and CENTRAL and hand-searched pertinent trial registers for eligible records until 5 August 2019. Results from individual studies were pooled using a random-effects model or described in a qualitative synthesis. The risk of bias was estimated with the tools provided by the Cochrane Collaboration (randomized and non-randomized trials) and the Evidence Project (single-arm trials). RESULTS: Four randomized controlled trials, two non-randomized controlled trials and two single-arm studies with a total sample size of n = 170 patients were included. Trichloroacetic acid (TCA) plus Jessner's solution showed significantly lower participant complete clearance (RR 0.36, 95% CI: 0.14-0.90, two studies, I2  = 0%, P = 0.03) and lower lesion clearance (RR 0.92, 95% CI: 0.85-0.99, one study, P = 0.03) compared to 5-fluorouracil (5-FU) 5% cream. TCA as monotherapy showed lower lesion complete clearance (RR 0.75, 95% CI: 0.69-0.82, two studies, I2  = 7%, P < 0.001) and lower mean lesion reduction per patient compared to conventional photodynamic therapy (cPDT) (MD -20.48, 95% CI: -31.55 to -9.41, two studies, I2  = 43%, P = 0.0003). Pain was more pronounced in patients treated with cPDT in comparison with TCA (MD -1.71 95% CI: -3.02 to -0.41, two studies, I2  = 55%, P = 0.01). In the single-arm studies, 5-FU plus glycolic acid showed 92% lesion clearance and phenol peeling 90.6% participant complete clearance. All studies showed a high risk for bias. CONCLUSIONS: Future high-quality studies and a standardization of peeling protocols are warranted to determine the value of chemical peelings in the treatment of AK.

Effectiveness, safety and utilization of vismodegib in locally advanced basal cell carcinoma under real-world conditions in Germany - The non-interventional study NIELS.

BACKGROUND: Basal cell carcinoma (BCC) can arise by the uncontrolled proliferation of cells from multiple epidermal compartments due to aberrant activation of the Hedgehog (Hh) signalling pathway. Vismodegib, a small-molecule inhibitor of this pathway, is approved for treatment of patients with locally advanced (la) BCC inappropriate for surgery or radiotherapy or patients with symptomatic metastatic (m) BCC. OBJECTIVES: The aim of this non-interventional study was to assess effectiveness with a special focus on duration of response (DOR), safety and utilization of vismodegib for treatment of laBCC in daily practice in Germany. METHODS: This non-interventional study (NIS) observed treatment of laBCC with vismodegib according to the German label in clinical practice. All available patients who had received at least one dose of vismodegib between commercial availability of vismodegib in Germany (02 August 2013) and 3 years before end of study (31 March 2016) could be included and were documented retrospectively and/or prospectively for up to 3 years. Primary effectiveness variable was DOR. Assessment of tumour response was carried out by the treating physicians. Exploratory variables included utilization of vismodegib, decision makers for therapy and method of tumour response evaluation. All statistical analyses were descriptive. RESULTS: Between September 2015 and March 2019, 66 patients were observed at 26 German centres. The objective response rate (ORR) was 74.2% and the disease control rate (DCR) was 90.9%. The median DOR was 15.9 months (95% CI: 9.2; 25.7; n = 49 patients with response). The median progression-free survival (PFS) was 19.1 months and the median time to response (TTR) 2.7 months. A total of 340 adverse events were reported in 63 (95.5%) patients; no new safety signals were identified. CONCLUSIONS: The NIS NIELS shows effectiveness and safety of vismodegib in patients with laBCC. It confirms the transferability of the results of the pivotal trial into routine clinical practice.

The more the better? An appraisal of combination therapies for actinic keratosis.

Actinic keratoses (AK) are common precancerous lesions of the skin. Numerous interventions exist for the treatment of AK, including lesion- and field-directed approaches. In daily practice, different treatment modalities are often combined to maximize clearance rates. However, whether a combination therapy is preferable to monotherapy in terms of efficacy and safety has been subject of intense debate. In this review, we summarize the current knowledge on the efficacy and safety of local combination therapies for the treatment of patients with AK. Combination approaches of cryosurgery followed by photodynamic therapy (PDT), laser-assisted PDT, PDT in combination with topical interventions and microneedling-assisted PDT have shown slightly better efficacy results with similar tolerability compared to the respective monotherapy. However, the individual usage of combination therapies should be checked on a case-by-case basis and take into account individual patient- and lesion-specific aspects as more resources are needed and because the individual monotherapies are already highly effective.

[Actinic keratosis]. / Aktinische Keratosen.

Actinic keratoses (AK) are common precancerous cutaneous lesions in fair-skinned individuals as a result of cumulative exposure to ultraviolet radiation. Due to their high prevalence, AK account for a large disease burden, in particular in older persons. As AK may potentially progress into invasive cutaneous squamous cell carcinoma, guidelines recommend early and consequent treatment. Numerous lesion- and field-directed interventions with different efficacy and safety profiles are currently licensed in Germany. The appropriate intervention should be chosen together with the patient based on his or her motivation and expectations towards the treatment.

[Actinic keratoses : Current guideline and practical recommendations]. / Aktinische Keratosen : Aktuelle Leitlinie und praxisbezogene Empfehlungen.

The S3 guideline "Actinic keratosis and squamous cell carcinoma of the skin" was published on 30 June 2019. Subsequently, publications, reviews and meta-analyses appeared with new questions regarding the comparability of study data and heterogeneity of the evaluations, which are caused, among other things, by divergent measurement parameters as well as insufficient consideration of pretreatments and combined treatments. This concise overview was written in the context of criticism and in view of necessary developments and research. Topics include epidemiology, pathogenesis, prevention, clinical presentation, therapy and BK5103. Therapy is divided into local destructive procedures and topical applications. Recommendations with quotation marks are based on the actual guideline. Corresponding evidence levels are given. For the implementation in daily routine basic data, side effects and features of therapeutic options are mentioned. The current developments and questions concerning actinic keratoses become clear.

[Cutaneous squamous cell carcinoma]. / Kutanes Plattenepithelkarzinom.

Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers of the Caucasian population and accounts for 20% of all skin tumours. An S3 guideline of the German Guideline Program in Oncology has been available since 2019. The diagnosis is based on the clinical examination. Excision and histological confirmation is required for all clinically suspicious lesions to allow prognostic assessment and correct treatment. The therapy of first choice is complete excision with histological control of the surgical margin. In cSCC with risk factors such as tumor thickness >6 mm, sentinel lymph node biopsy may be discussed, but there is currently no clear evidence of its prognostic and therapeutic relevance. Adjuvant radiation therapy may be considered in cases of high risk of recurrence and should be tested in cases of inoperable tumors. The indication for electrochemotherapy should also be considered in the treatment of local or locoregional recurrence. The immune checkpoint inhibitor cemiplimab is approved for the treatment of inoperable or metastasized cSCC. In case of contraindications, chemotherapeutic agents, epidermal growth factor receptor (EGFR) inhibitors or palliative radiotherapy can be used. Since the evidence is low in these cases, a systemic therapy should be used preferentially within clinical studies. Follow-up care should be risk-adapted and includes a dermatological control, supplemented by ultrasound examinations in high-risk patients.

Cryosurgery combined with topical interventions for actinic keratosis: a systematic review and meta-analysis.

BACKGROUND: Actinic keratoses (AKs) are early in situ carcinomas of the skin caused by cumulative sun exposure. Cryosurgery is an easy and practicable lesion-directed approach for treatment of isolated lesions. OBJECTIVES: To investigate whether an upfront combination of cryosurgery with a topical intervention is superior to cryosurgery alone for treatment of AK. METHODS: We performed a systematic literature search in MEDLINE, Embase and CENTRAL and hand searched pertinent trial registers for eligible randomized controlled trials until 17 July 2018. Results from individual studies were pooled using a random effects model. The risk of bias was estimated with the Cochrane Risk of Bias Tool and the quality of evidence of the outcomes with the GRADE approach. RESULTS: Out of 1758 records initially identified, nine studies with a total sample size of 1644 patients were included. Cryosurgery in combination with a topical approach showed significantly higher participant complete clearance rates than monotherapy [risk ratio (RR) 1·74, 95% confidence interval (CI) 1·25-2·43, I2 = 73%, eight studies]. The participant partial clearance rate was not statistically different (RR 1·64, 95% CI 0·88-3·03, I2 = 77%, three studies). The number of patients who completed the study protocol and did not withdraw due to adverse events was equal in both groups (RR 0·98, 95% CI 0·95-1·01, I2 = 75%, seven studies). The studies were estimated to have high risk for selective reporting bias. CONCLUSIONS: Our results suggest the superiority of a combination regimen for AK clearance, with equal tolerability. This study highlights the importance of a field-directed approach in patients with multiple AKs or field cancerization.

Local interventions for actinic keratosis in organ transplant recipients: a systematic review.

BACKGROUND: Actinic keratosis (AK) in organ transplant recipients (OTRs) has a high risk of progressing to invasive squamous cell carcinoma of the skin. Thus, early and consequent treatment of AKs is warranted in OTRs. OBJECTIVES: To summarize the current evidence for nonsystemic treatments of AKs in OTRs. METHODS: We performed a systematic literature search in MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) and hand-searched pertinent trial registers up to 22 August 2018. Randomized controlled trials (RCTs) evaluating nonsystemic interventions for AKs in OTRs were included. The risk of bias was estimated using the Cochrane Risk of Bias Tool. RESULTS: Of 663 records initially identified, eight RCTs with 242 OTRs were included in a qualitative synthesis. Most studies evaluated methyl aminolaevulinate photodynamic therapy (MAL-PDT), followed by ablative fractional laser (AFXL) and diclofenac sodium 3% in hyaluronic acid, imiquimod 5% cream and 5-fluorouracil 5% cream (5-FU). MAL-PDT showed the highest rates of participant complete clearance (40-76·4%), followed by imiquimod (27·5-62·1%), diclofenac (41%) and 5-FU (11%). Similar results were observed for lesion-specific clearance rates. Treatment with AFXL alone revealed low lesion clearance (5-31%). Local skin reactions were most intense in participants treated with a combination of AFXL and daylight MAL-PDT. There were no therapy-related transplant rejections or worsening of graft function in any trial. The overall risk of bias was high. CONCLUSIONS: Limited evidence is available for the treatment of AKs in OTRs. MAL-PDT is currently the best-studied intervention. Lesion-specific regimens may not be sufficient to achieve disease control. Field-directed regimens are preferable in this high-risk population.

Comparison of guidelines for the management of patients with high-risk and advanced cutaneous squamous cell carcinoma - a systematic review.

The management of high-risk cutaneous squamous cell carcinoma (cSCC) can be a challenge as evidence from high quality clinical trials is rare. Guideline developers are challenged to provide practical and useful guidance for clinicians even in the absence of good evidence. In order to compare treatment recommendations for high-risk and advanced cSCC among national and international guidelines and to extract the most precise guidance provided, a systematic search was carried out in guideline databases Medline and Embase with a cutoff of 4 March 2019. Treatment recommendations for predefined clinical scenarios were extracted from selected guidelines and compared qualitatively. Five guidelines published from 2015 to 2018 were included. Excision of high-risk tumours with margin assessment was recommended in all guidelines. A safety margin of at least 6 mm was suggested in four guidelines. There was no clear recommendation to perform a sentinel lymph node biopsy in any guideline. Lymph node dissection was uniformly recommended in the presence of nodal disease. Treatment for metastatic cSCC was poorly characterized and restricted to the use of chemotherapy and epidermal growth factor receptor inhibitors. Recommendations for the management of high-risk and advanced cSCC were limited. We propose that guidelines should be updated to reflect recent advances in checkpoint blockade for metastatic cSCC.

Efficacy of photodynamic therapy combined with topical interventions for the treatment of actinic keratosis: a meta-analysis.

BACKGROUND: Photodynamic therapy (PDT) is a highly effective treatment option for patients with actinic keratoses (AK). However, efficacy can be reduced by insufficient illumination or hyperkeratotic nature of lesions. OBJECTIVES: To investigate if PDT combined with a topical intervention is superior to monotherapy in terms of efficacy and tolerability. METHODS: A systematic literature research was conducted in Medline, Embase and CENTRAL. Pertinent trial registers were hand-searched for eligible randomized controlled trials (RCTs) until 20 August 2018. Results were pooled using a random effects model to calculate relative risks (RR) or mean differences. The risk of bias was assessed with the Cochrane Risk of Bias Tool. The quality of evidence was estimated for each outcome of interest according to GRADE. RESULTS: Out of 1800 references initially identified, 10 RCTs with a total sample size of n = 277 were included. Four studies investigated a combination of PDT with imiquimod cream, three with 5-fluorouracil cream and one each with ingenol mebutate gel, tazarotene gel and calcipotriol ointment, respectively. Patients treated with a combination showed higher participant complete (RR 1.63; 95% CI 1.15-2.33; P = 0.007) and partial clearance rates (RR 1.19; 95% CI 0.84-1.67; P = 0.33). Similarly, the lesion-specific clearance was higher for PDT plus topical intervention compared to monotherapy (RR 1.48; 95% CI 1.04-2.11; P = 0.03). A subgroup analysis was performed for PDT combined with imiquimod, revealing an increased participant complete clearance rate compared to monotherapy (RR 1.57, 95% CI 1.09-2.25, P = 0.02). PDT-induced pain and local skin reactions after treatment were poorly reported. The studies were estimated at high risk for performance and detection bias. CONCLUSION: The combination of PDT with another topical drug intervention does improve AK clearance rates compared to either monotherapy alone. This study highlights that the sequential application of two field-directed treatments represents an efficient approach in patients with multiple AK and field cancerization.

Optical coherence tomography of basal cell carcinoma: influence of location, subtype, observer variability and image quality on diagnostic performance.

BACKGROUND: We previously described the principal results from an observational, prospective, multicentre, clinical trial of the diagnostic value of optical coherence tomography (OCT) for basal cell carcinoma (BCC) in a clinical setting. In this trial, much additional useful information was gathered that warranted further analysis, presented here. OBJECTIVES: To investigate the influence of candidate diagnostic criteria, OCT image quality, lesion location, and observer confidence and interobserver variability on the diagnostic performance of OCT, and to assess its potential use for diagnosis of BCC subtypes. METHODS: A total of 234 clinically unclear 'pink lesions' were evaluated in three steps: after clinical examination, after adding dermoscopy and after adding OCT. In addition to the diagnoses (including lesion subtype), observers recorded which of 15 diagnostic criteria the OCT image contained, their confidence in the diagnoses, the OCT image quality and the anatomical location of the lesion. RESULTS: Diagnostic performance of OCT did not depend on the lesion's anatomical location. Good OCT image quality was correlated with improved diagnostic performance, but diagnostic performance for lesions with mediocre image quality was still better than by clinical and dermoscopic examination. The main reason for reduced image quality was superficial scales and crusting. Observer confidence in diagnosis was correlated with diagnostic performance. Interobserver diagnostic performance was consistently higher than clinical examination and dermoscopy across all sites. BCC subtype could be determined with moderate accuracy, but further independent image markers are required. CONCLUSION: OCT is useful in the diagnosis of BCC.

A randomized, multinational, noninferiority, phase III trial to evaluate the safety and efficacy of BF-200 aminolaevulinic acid gel vs. methyl aminolaevulinate cream in the treatment of nonaggressive basal cell carcinoma with photodynamic therapy.

BACKGROUND: Basal cell carcinoma (BCC) represents the most common nonmelanoma skin cancer worldwide, affecting mainly adult, fair-skinned individuals. The World Health Organization distinguishes aggressive and nonaggressive forms, of which prototypical variants of the latter are primary nodular and superficial BCC. OBJECTIVES: To demonstrate noninferiority of BF-200 ALA (a nanoemulsion gel containing 5-aminolaevulinic acid) compared with MAL (a cream containing methyl aminolaevulinate) in the treatment of nonaggressive BCC with photodynamic therapy (PDT). Noninferiority of the primary efficacy variable (overall patient complete response 12 weeks after last PDT) would be declared if the mean response for BF-200 ALA was no worse than that for MAL, within a statistical margin of Δ = -15%. METHODS: The study was a randomized, phase III trial performed in Germany and the U.K. with ongoing 5-year follow-up. Of 281 randomized patients, 138 were treated with BF-200 ALA and 143 with MAL. Patients received two PDT sessions 1 week apart. Remaining lesions 12 weeks after the second PDT were retreated. Illumination was performed with a red light source (635 nm, 37 J cm-2 ). The results shown include clinical end points and patients' reassessment 12 months after the last PDT. The study was registered with EudraCT (number 2013-003241-42). RESULTS: Of the BF-200 ALA-treated patients, 93·4% were complete responders compared with 91·8% in the MAL group. The difference of means was 1·6, with a one-sided 97·5% confidence interval of -6·5, establishing noninferiority (P < 0·0001). The results for secondary efficacy parameters were in line with the primary outcome. Recurrence rates 12 months after the last treatment were ≤ 10%. CONCLUSIONS: Treatment of nonaggressive BCC with BF-200 ALA-PDT is highly effective and well tolerated with proven noninferiority to MAL-PDT. It demonstrates low recurrence rates after 1 year of follow-up.

[Information services for melanoma patients and awareness among those affected]. / Informationsangebote für Melanompatienten und ihre Bekanntheit unter Betroffenen.

BACKGROUND: Besides medical consultations, various sources of information and support are available for melanoma patients (MP) in Germany from commercial and non-commercial providers; however, little is known about how they are perceived and accepted by MPs. MATERIAL AND METHODS: Between July and October 2016 a total of 529 melanoma patients were surveyed at 27 accredited German skin cancer centers by means of a standardized questionnaire. Their awareness and satisfaction with 12 given sources of information and counseling services (print, online and by telephone) were surveyed. The sources were recommended by renowned providers from the field of (dermatological) oncology for use by MPs. RESULTS: The MPs reported that the booklets called The blue advisor - skin cancer (Die Blauen Ratgeber - Hautkrebs, 43%) and Patient guidelines melanoma (Patientenleitlinie Melanom 24%) and the online domain www.hautkrebs-screening.de (23%) were the best known sources. These also met the information needs of the majority of users (65-80%). Booklets from commercial providers (between 8-16% known) were satisfactory for 42-56% of users. At 14% and 11%, respectively, the cancer counseling services (Krebsinformationsdienst) and INFONETZ Krebs as mainly telephone advisory offers were less well known. Few MPs were familiar with the skin cancer or melanoma booklets of the Austrian Cancer Aid and the Swiss Cancer League (2% each). CONCLUSION: The increased awareness and acceptance of booklets as well as information from principally non-commercial providers suggest that they are more often mediated to MPs and more frequently used and accepted by those affected.

Efficacy and safety of nilotinib in patients with KIT-mutated metastatic or inoperable melanoma: final results from the global, single-arm, phase II TEAM trial.

BACKGROUND: The single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment. PATIENTS AND METHODS: Forty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC before the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors. RESULTS: ORR was 26.2% (n = 11/42; 95% CI, 13.9%-42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease and 10 (23.8%) had progressive disease; 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, four with an L576P mutation. The median progression-free survival and overall survival were 4.2 and 18.0 months, respectively. Three of the 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib. CONCLUSION: Nilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01028222.

The impact of sentinel node dissection on disease-free and overall tumour-specific survival in melanoma patients: a single centre group-matched analysis of 1192 patients.

BACKGROUND: Sentinel lymph node dissection (SLND) is considered a standard staging procedure providing important prognostic information on melanoma patients. It remains a matter of debate, whether SLND and hence, removal of potential lymph node micrometastasis will alter survival outcome. OBJECTIVE: The aim of this group-matched analysis was to compare survival data of a large cohort of melanoma patients who were treated by wide local excision only (WLE) and nodal observation (WLE group) to a group of patients treated with WLE plus SLND group to investigate the potential therapeutic benefit of SLND in the treatment of patients with melanoma. METHODS AND MATERIALS: A total of 596 consecutive patients who had undergone WLE plus SLND between 1996 and 2003 were assessed. As a historical control group 596 patients treated with WLE and nodal observation but without SLND between 1986 and 1995 were selected. The groups were matched according to sex, age, Breslow tumour thickness and localization of primary tumour. The adjuvant treatment and follow-up examinations were performed according to protocols of the German Dermatologic Cooperative Oncology Group (DeCOG) and applicable study protocols that our clinic participated in; and hence, subject to change over time. RESULTS: Kaplan-Meier testing revealed significant differences in survival in favour of the SLND group. Mean overall tumour-specific survival (OS) was 102.7 months in the SLND group vs. 97.0 months in the WLE group respectively (P-value: 0.024). Disease-free survival (log-rank test: 0.003) and time to lymph node progression (P-value: <0.01) also differed significantly between the two groups. CONCLUSION: SLND is not only an important diagnostic procedure, but might also be of therapeutic benefit in terms of disease-free and overall tumour-specific survival of melanoma patients.

[Stable disease or complete response? : A critical evaluation of the radiologic response to immune checkpoint blockade in advanced melanoma]. / Stabile Erkrankung oder vollständiges Ansprechen? : Evaluation der radiologischen Interpretation des Therapieansprechens auf Immune-Checkpoint-Blockade im metastasierten malignen Melanom.

BACKGROUND: Rating the response of melanoma to immune checkpoint blockade (ICB) by conventional CT proves to be difficult, since response patterns and kinetics differ from the classical responses seen with other therapies. Hence, immune-related response criteria were developed. However, they are mainly based on the alteration of the diameter of lesions over time but do not include metabolic activity. OBJECTIVE: The aim of this study was to search for additional criteria to improve the interpretation of the radiologic images of patients with metastatic melanoma after ICB. MATERIALS AND METHODS: We retrospectively analysed 7 patients with metastatic melanoma over a period of 13-41 months after treatment with ICB using contrast enhanced CT scans from the neck region to the lower abdomen and compared the results in the follow ups with 18F-FDG PET/CT. RESULTS: Metastatic lesions in 5 of 7 patients rated as stable disease (SD) in CT staging showed no metabolic activity in 18F-FDG PET/CT. The size of these lesions did not increase or show metabolic activity in the further follow-up, even after discontinuation of ICB. In contrast, tumor lesions in the other 2 patients rated as SD in CT staging showed metabolic activity in 18F-FDG PET/CT. These tumor lesions expanded significantly in the further course of the disease. CONCLUSION: In addition to the size of a tumor lesion, its metabolic activity adds important information regarding treatment response. Thus, we propose that the metabolic activity assessed with 18F-FDG-PET/CT should be included in the immune response criteria. No FDG uptake in a lesion should be rated as inactive tumor rather than SD and further treatment may not be required.

Adjuvant treatment with pegylated interferon α-2a versus low-dose interferon α-2a in patients with high-risk melanoma: a randomized phase III DeCOG trial.

BACKGROUND: Adjuvant treatment with interferon (IFN)-α-2a improved disease-free survival (DFS) and showed a trend for improving overall survival (OS) in melanoma. This trial was designed to examine whether PEG-IFN is superior to IFN with regard to distant metastasis-free survival (DMFS), DFS and OS. PATIENTS AND METHODS: In this multicenter, open-label, prospective randomized phase III trial, patients with resected cutaneous melanoma stage IIA(T3a)-IIIB (AJCC 2002) were randomized to receive PEG-IFN (180 µg subcutaneously 1×/week; 24 months) or IFN α-2a (3MIU subcutaneously 3×/week; 24 months). Randomization was stratified for stage, number of metastatic nodes, age and previous IFN treatment. The primary end point was DMFS; secondary end points were OS, DFS, quality of life (QoL) and tolerability. RESULTS: A total of 909 patients were enrolled (451 PEG-IFN versus 458 IFN). Neither 5-year DMFS [PEG-IFN 61.0% versus IFN 67.3%; hazard ratio (HR) 1.16, P = 0.21] nor 5-year OS (PEG-IFN 73.2% versus IFN 75.2%; HR 1.05, P = 0.70) nor 5-year DFS (PEG-IFN 57.3% versus IFN 60.9%; HR 1.09, P = 0.40) showed significant differences. Subgroup analyses in patients ± ulcerated primaries and of different tumor stages did not find differences in DMFS, OS or DFS between the treatment groups. One hundred and eighteen patients (26.2%) in the PEG-IFN and 61 patients (13.3%) in the IFN population did not receive the full dosage and length of treatment due to adverse events (P < 0.001). Leukopenia and elevation of liver enzymes were more common in the PEG-IFN arm (56% versus 23.5% LCP; 19.1% versus 9.4% AST; 33.0% versus 16.5% ALT). QoL was identical for nearly all domains. CONCLUSION: PEG-IFN did not improve the outcome over IFN. A higher percentage of patients under PEG-IFN discontinued treatment due to toxicity. CLINICAL TRIALSGOV IDENTIFIER: NCT00204529.