Previous radiotherapy improves treatment responses and causes a trend toward longer time to progression among patients with immune checkpoint inhibitor-related adverse events.

BACKGROUND: Immune-related adverse events (irAEs) are frequently encountered by patients during immune checkpoint inhibitor (ICI) treatment and are associated with better treatment outcomes. The sequencing of radiotherapy (RT) and ICIs is widely used in current clinical practice, but its effect on survival has remained unclear. METHODS: In a real-world multicenter study including 521 patients who received ICI treatment for metastatic or locally advanced cancer, RT schedules and timing, irAEs, time to progression, overall survival, and treatment responses were retrospectively reviewed. RESULTS: Patients who received previous RT and developed irAE (RT +/AE +) had the best overall response rate (ORR 44.0%). The ORR was 40.1% in the RT -/AE + group, 26.7% in the RT -/AE - group and 18.3% in the RT + /AE - group (p < 0.001). There was a significantly longer time to progression (TTP) in the RT + /AE + group compared to the RT -/AE - and RT + /AE - groups (log rank p = 0.001 and p < 0.001, respectively), but the trend toward longer TTP in the RT + /AE + group did not reach statistical significance in pairwise comparison to that in the RT -/AE + group. Preceding RT timing and intent had no statistically significant effect on TTP. In a multivariate model, ECOG = 0 and occurrence of irAEs remained independent positive prognostic factors for TTP (HR 0.737; 95% CI 0.582-0.935; p = 0.012, and HR 0.620; 95% CI 0.499-0.769; p < 0.001, respectively). CONCLUSIONS: Better ORR and a trend toward longer TTP were demonstrated for patients with RT preceding ICI treatment and development of irAEs, which suggests that RT may boost the therapeutic effect of immunotherapy in patients with metastatic cancers.

Hot dots - which nodes should be removed in sentinel lymph node biopsy for melanoma?

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a critical staging tool for melanoma patients. The optimal number of lymph nodes removed in SLNB remains unclear. In this study, we retrospectively analysed and tested different criteria for selecting sentinel lymph nodes (SLNs) by radiotracer uptake and blue dye, and their impact on nodal staging. We also evaluated the association between SLN tumour burden and radiotracer uptake. METHODS: The study population consisted of melanoma patients undergoing SLNB. During the operation all radioactive and blue nodes were removed and sent for histopathological analysis. The ex vivo radioactive count and presence of blue dye of each node were recorded, and these were correlated with presence and size of metastasis in each SLN. RESULTS: Altogether 175 patients with clinically occult metastasis presented with one or more positive, i.e. metastatic, SLNs. The mean number of lymph nodes removed was 4.5, and the mean number of positive lymph nodes was 1.5 per patient. The most radioactive or hottest node was negative in 38 patients (22%). By removing the hottest node and all nodes with radioactivity >10% of the hottest node, 97% of patients would have been staged correctly. In five patients, metastasis was found solely in a SLN with radioactivity <10% of the hottest node. Of all 267 positive nodes removed, 125 (47%) contained blue dye. Patients with a negative hottest node were associated with lower SLN tumour burden. CONCLUSIONS: By removing the hottest node and all nodes with radioactivity >10% of the hottest node, 97% of patients with SLN metastases are correctly staged with or without using blue dye.

Circulating tumor DNA is a prognostic biomarker in metastatic melanoma patients treated with chemoimmunotherapy and BRAF inhibitor.

BACKGROUND: Detectable circulating tumor DNA (ctDNA) has been associated with worse prognosis in melanoma patients. MATERIAL AND METHODS: We studied plasma ctDNA as a prognostic biomarker in 19 patients with metastatic melanoma and a detectable tumor mutation (13 BRAF, 5 NRAS, and 1 KRAS). Patients had received chemotherapy, interferon-alpha, and vemurafenib in a prospective clinical trial. Mutant allele frequency (MAF %) was determined with droplet digital PCR from pretreatment and sequential plasma samples. RESULTS: Higher pretreatment plasma ctDNA levels (MAF ≥3%) and detectable plasma ctDNA levels (MAF >0%) at the time of radiologically confirmed best objective response were associated with poor prognosis even when accounting for other relevant prognostic factors including performance status, tumor mutation, metastasis stage, and lactate dehydrogenase levels in multivariable analysis. CONCLUSION: Higher pretreatment plasma ctDNA levels and sustained detectable plasma ctDNA levels during treatment indicated poor prognosis in metastatic melanoma patients.

Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy.

The SAKK 35/10 phase 2 trial, developed by the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, compared the activity of rituximab vs rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m2 IV on day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end point was complete response (CR)/unconfirmed CR (CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular Lymphoma International Prognostic Index score in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%; 95% confidence interval [CI], 26%-48% vs 25%; 95% CI, 16%-36%) and confirmed by an independent response review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% CI, 26%-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates and longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (≥90%). Toxicity grade ≥3 was more common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia (23% vs 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored. This trial was registered at www.clinicaltrials.gov as #NCT01307605.

Different expression of BRAFV600E, ALK and PD-L1 in melanoma in children and adolescents: a nationwide retrospective study in Finland in 1990-2014.

BACKGROUND: Pediatric melanoma may have a different biological background and more favorable prognosis compared with melanoma in adults. The aim of this study was to investigate melanoma in children and adolescents in the Finnish population in terms of incidence, clinical course, treatment, prognosis and BRAFV600E-, ALK- and PD-L1-positivity of the primary tumors. MATERIALS AND METHODS: Primary tumor samples and clinical records of all patients aged 0-19 years diagnosed with cutaneous melanoma in Finland in 1990-2014 were collected using the Finnish Cancer Registry database, Finnish hospitals and private pathology laboratories. BRAFV600E, ALK and PD-L1 were analyzed from 54 primary tumors and BRAFV600E from six metastasis samples. RESULTS: A total of 122 patients diagnosed with cutaneous melanoma were retrieved from the Cancer Registry database. The primary tumor samples of 73 patients were obtained for the review, and 56 cases were included in the study. The incidence of pediatric melanoma increased from 0.02 to 0.1/100 000 during the period 1990-2014. Spitzoid melanoma was the most common subtype (66%). The 10-year cancer-specific survival (CSS) was 88.7% in all patients. The 10-year-CSS did not differ in SLNB-positive or -negative groups. BRAFV600E was positive in 48%, ALK in 9% and PD-L1 in 2% of the tumors. BRAFV600E mutation was associated with 83% of melanoma deaths. CONCLUSIONS: Young melanoma patients had more favorable prognosis and a different staining profile for BRAFV600E, ALK, and PD-L1 in primary tumor than reported in adults. SLNB status was not an indicator for survival. BRAFV600E-positive patients have worse prognosis and could benefit from surveillance and treatment similarly to adults.

Age-associated changes in the immune system may influence the response to anti-PD1 therapy in metastatic melanoma patients.

Anti-PD1 treatment has improved the survival of metastatic melanoma patients, yet it is unknown which patients benefit from the treatment. In this exploratory study, we aimed to understand the effects of anti-PD1 therapy on the patients' immune system and discover the characteristics that would result in successful treatment. We collected peripheral blood (PB) samples from 17 immuno-oncology-naïve metastatic melanoma patients before and after 1 and 3 months of anti-PD1 therapy. In addition, matching tumor biopsies at the time of diagnosis were collected for tissue microarray. The complete blood counts, PB immunophenotype, serum cytokine profiles, and tumor-infiltrating lymphocytes were analyzed and correlated with the clinical data. Patients were categorized based on their disease control into responders (complete response, partial response, stable disease > 6 months, N = 11) and non-responders (progressive disease, stable disease ≤ 6 months, N = 6). During therapy, the PB natural killer T (NKT) cell frequency, expression of CD25 and CD45RO on cytotoxic natural killer (NK) cells, and serum CXC chemokine levels were significantly increased in responders. Furthermore, higher age together with age-associated characteristics from PB, lower frequency of PB-naïve CD8+ T cells, and elevated levels of serum MCP-4 and OPG were discovered as baseline predictors of treatment response. We therefore propose that in addition to T cells, anti-PD1 treatment is associated with NK- and NKT-cell population dynamics, and that the age-associated characteristics from PB together with older age may contribute to prolonged PFS in anti-PD1-treated melanoma patients.

Limited-duration anti-PD-1 therapy for patients with metastatic melanoma.

Purpose: To date, no clinical study has reported on the optimal treatment duration of PD-1 blockade in patients with metastatic melanoma. Worldwide, concern has been expressed that due to the high cost of anti-PD-1 therapy, it is not available for all patients. After approval of anti-PD-1 therapy as a first-line treatment, the Helsinki University Hospital institutional board for new drugs decided to treat the first patient cohort within a limited treatment duration program in order to offer this treatment to as many patients as possible.Patients and methods: The first 40 patients with metastatic melanoma initiating treatment at Helsinki University Hospital were to be treated within a six months maximum limited duration program. Patient follow-up was systematic according to a prospectively planned treatment protocol to enable evaluation of treatment efficacy and the safety of this treatment approach.Results: Thirty-eight patients were treated within the program. Seventeen out of these 38 patients completed the six-month regimen. Five discontinued treatment early due to toxicity, and 16 discontinued due to progressive disease. The response rate (RR) for all patients was 39%, but only 33% of these responses are ongoing. Median progression-free survival (PFS) for patients who completed the six-month therapy was 12 months (range, two to 44 months), and median overall survival (OS) has not yet been reached.Conclusions: Although RR is comparable to published data, the response duration is shorter. Based on our results, limiting treatment to only six months may increase the risk of shortening response duration.

Nivolumab in previously untreated melanoma without BRAF mutation.

BACKGROUND: Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study. METHODS: We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival. RESULTS: At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine. CONCLUSIONS: Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.).

Selective internal radiation therapy (SIRT) as treatment for hepatic metastases of uveal melanoma: a Finnish nation-wide retrospective experience.

BACKGROUND: In Finland, selective internal radiation therapy (SIRT) is at present the preferred first-line loco-regional therapy for uveal melanoma patients with hepatic metastases not suitable for surgery. We retrospectively evaluate the outcome and safety of SIRT in this group of patients. MATERIAL AND METHODS: Yttrium-90 microspheres were delivered via the hepatic artery into the circulation of metastases from uveal melanoma in 18 patients with a predicted life expectancy of more than three months in three Finnish tertiary referral centers between November 2010 and December 2015. Progression-free survival (PFS), toxicity and overall survival (OS) were evaluated. Patients with historical uveal melanoma without extrahepatic metastases, who had received systemic chemotherapy as first-line treatment for their hepatic metastases at the Helsinki University Hospital between January 2006 and May 2010, were used as a historical control group. RESULTS: Partial response and stable disease were observed in three (17%) and eight (44%) patients, respectively; one patient was not evaluable for response. Median PFS after SIRT was 5.6 (range, 1.3-40.8) months. Median OS after SIRT was 13.5 (range, 3.6-44.8) months compared with 10.5 (range, 3.0-16.5; p = .047) months for the historical chemotherapy group. Among patients who received SIRT as first-line treatment, the median OS was 18.7 (range, 8.2-44.8) months, significantly longer than that of the chemotherapy group (10.5 months, p = .017). There were no treatment-related deaths. Toxicity was mainly WHO grade 1-2 and self-limited. CONCLUSION: SIRT is a feasible and safe treatment for liver metastases in patients with uveal melanoma.

[Adverse effects of new immunologic drugs for melanoma and their management in adult patients]. / Uusien immunologisten melanoomalääkkeiden haittavaikutukset ja niiden hallinta.

Conventional anticancer drugs, cytotoxic agents, function by killing all rapidly dividing cells without distinguishing between cancer cells and normal cells of the body. Understanding of the regulatory mechanisms of the immune system has enabled the development of immunotherapeutic drugs and, through them, liberation of the immune response for the management of cancer. In Finland, interferons and antibody therapies represent the clinically applied immunotherapy of melanoma. While most antibody therapies are fairly harmless, the new drugs enhancing T cell defense are associated with a significant risk of autoimmune adverse effects. Immediate recognition and treatment of adverse effects are essential for the survival of the patients.

Benefit of adjuvant interferon alfa-2b (IFN-α) therapy in melanoma patients with high serum MMP-8 levels.

Matrix metalloproteinases (MMPs) are important enzymes in tissue turnover and various inflammatory processes. In this study, it was evaluated whether serum MMP-8 can predict the response to adjuvant interferon alfa-2b (IFN-α) therapy in patients with operated high-risk cutaneous melanoma. Pre-treatment sera from 460 patients with stage IIB-IIIC melanoma were analyzed for MMP-8. The patients were randomized after surgery to adjuvant IFN-α for 12 or 24 months (n = 313) or observation only (n = 147). The median serum MMP-8 level was used to classify the patients into a low MMP-8 (n = 232) and a high MMP-8 (n = 228) group. In the high MMP-8 subgroup, IFN-α therapy significantly improved relapse-free survival (RFS). RFS was 36.8 months in patients with high MMP-8 levels receiving IFN-α therapy, whereas RFS for those with high MMP-8 levels with observation only was 10.6 months (P = 0.027). Median overall survival for patients with high MMP-8 and observation only was 36.7 versus 71.7 months in those receiving IFN-α (P = 0.13). In a multivariate model, IFN-α therapy was a significant predictor of favorable RFS (HR 0.74; 95 % CI 0.55-0.99; P = 0.048), after adjustment for pre-treatment MMP-8 (HR 1.17; 95 % CI 0.88-1.55; P = 0.28), gender (HR 1.16; 95 % CI 0.86-1.56; P = 0.32), age (HR 1.00; 95 % CI 1.00-1.02; P = 0.12), ulceration (HR 1.09; 95 % CI 0.81-1.46; P = 0.58), and the presence of node metastases (HR 1.36; 95 % CI 1.17-1.58; P < 0.0001). In conclusion, patients with high serum MMP-8 levels may benefit from adjuvant IFN-α therapy, but this observation should be further investigated.

Determinants of Long-Term Survival in Metastatic Choroidal and Ciliary Body Melanoma.

PURPOSE: To build and validate a prognostic model that predicts long-term overall survival (OS) in metastatic choroidal and ciliary body melanoma (CCBM) to facilitate patient counseling and planning, reporting, and interpreting clinical trials. DESIGN: Retrospective cohort study with validation. METHODS: We analyzed predictors of intermediate (IMT; 25-<42 months) and long-term (LT; ≥42 months) OS in a Finnish nationwide cohort of 330 patients with metastatic CCBM. Short-term (<25 months), IMT, and LT survival were compared with pairwise and ordinal logistic regression. A single-center cohort of 259 patients from Italy was used for validation. Models were compared with a deviance test. RESULTS: Median OS was 12 and 17 months in the building and validation datasets, respectively; 40 (12%) and 31 (9%) compared with 44 (17%) and 32 (12%) patients were IMT and LT survivors, respectively. Alkaline phosphatase or lactate dehydrogenase level never exceeded 2 times the upper normal limit (UNL) in either LT cohort. Conditional to both being ≤2 times the UNL, distant metastasis-free interval (DMFI) >42 months (odds ratio [OR] 4.09-4.64; P < .001) paired with age <60 years (OR 3.23; P = .002), having no symptoms (OR 4.19; P = .005), and the largest diameter of the largest metastasis <30 mm (Tumor, Node, Metastasis stage M1a; OR 3.05; P = .001) independently predicted higher odds of surviving longer (IMT or LT) without model preference. These results were confirmed in the validation dataset. CONCLUSIONS: Alkaline phosphatase or lactate dehydrogenase >2 times the UNL essentially precluded LT survival. The most robust predictor otherwise was DMFI >42 months, followed by age <60 years, absence of symptoms, and Tumor, Node, Metastasis stage M1a.

Early clinical experience with a degraded 4 MeV electron beam in radiotherapy of superficial basal cell carcinoma.

The most common non-melanoma skin cancer is basal cell carcinoma (BCC). Surgery is the gold standard treatment but also non-surgical alternatives are needed. The purpose of this work was to present the early clinical experiences of degraded 4 MeV electron beam as a treatment method for superficial BCC. Twelve patients underwent two weeks radiation therapy treatment with either 5 × 7 Gy or 2 × 12 Gy. There were no significant differences in treatment outcome with different fractionations or lesion locations. The degraded beam method is a safe and valid non-surgical solution for suitable patients with superficial lesions.

Antibiotic Treatment is an Independent Poor Risk Factor in NSCLC But Not in Melanoma Patients Who had Received Anti-PD-1/L1 Monotherapy.

BACKGROUND: Antibiotic treatment may reduce the efficacy of cancer immunotherapy by disrupting gut microbiome. We aimed to study the association of antibiotics and survival outcomes in advanced cutaneous melanoma and non-small-cell lung cancer (NSCLC) patients who had received anti-PD-1/L1 monotherapy. PATIENTS AND METHODS: A total of 222 melanoma and 199 NSCLC patients had received anti-PD-1/L1 monotherapy in 5 Finnish hospitals between January 2014 and December 2020. Clinical characteristics, antibiotic and corticosteroid treatment, and survival outcomes were retrospectively collected from hospital and national medical records. RESULTS: There were 32% of melanoma and 31% of NSCLC patients who had received antibiotic treatment (ABT) 3 months before to 1 month after the first anti-PD-1/L1 antibody infusion. In survival analyses, early antibiotic treatment was associated with inferior overall survival (OS) (ABT 19.2 [17.6-43.7] vs. no ABT 35.6 [29.3-NA] months, P = .033) but not with inferior progression-free survival (PFS) (ABT 5.8 [3.0-12.6] vs. no ABT 10.2 [7.7-15.3] months, P = .3) in melanoma patients and with inferior OS (ABT 8.6 [6.4-12.3] vs. no ABT 18.5 [15.1-21.6] months, P < .001) and PFS (ABT 2.8 [2.1-4.5] vs. no ABT 5.6 [4.4-8.0] months, P = .0081) in NSCLC patients. In multivariable analyses, ABT was not an independent risk-factor for inferior OS and PFS in melanoma but was associated with inferior OS (hazard ratio [HR] 2.12 [1.37-3.28]) and PFS (HR 1.65 [1.10-2.47]) in NSCLC after adjusted for other risk factors. CONCLUSIONS: Early ABT was an independent poor risk factor in NSCLC patients who had received anti-PD-1/L1 monotherapy but not in melanoma patients. The weight of ABT as a poor risk factor might depend on other prognostic factors in different cancers.

Single-cell characterization of anti-LAG-3 and anti-PD-1 combination treatment in patients with melanoma.

BackgroundRelatlimab plus nivolumab (anti-lymphocyte-activation gene 3 plus anti-programmed death 1 [anti-LAG-3+anti-PD-1]) has been approved by the FDA as a first-line therapy for stage III/IV melanoma, but its detailed effect on the immune system is unknown.MethodsWe evaluated blood samples from 40 immunotherapy-naive or prior immunotherapy-refractory patients with metastatic melanoma treated with anti-LAG-3+anti-PD-1 in a phase I trial using single-cell RNA and T cell receptor sequencing (scRNA+TCRαß-Seq) combined with other multiomics profiling.ResultsThe highest LAG3 expression was noted in NK cells, Tregs, and CD8+ T cells, and these cell populations underwent the most significant changes during the treatment. Adaptive NK cells were enriched in responders and underwent profound transcriptomic changes during the therapy, resulting in an active phenotype. LAG3+ Tregs expanded, but based on the transcriptome profile, became metabolically silent during the treatment. Last, higher baseline TCR clonality was observed in responding patients, and their expanding CD8+ T cell clones gained a more cytotoxic and NK-like phenotype.ConclusionAnti-LAG-3+anti-PD-1 therapy has profound effects on NK cells and Tregs in addition to CD8+ T cells.Trial registrationClinicalTrials.gov (NCT01968109)FundingCancer Foundation Finland, Sigrid Juselius Foundation, Signe and Ane Gyllenberg Foundation, Relander Foundation, State funding for university-level health research in Finland, a Helsinki Institute of Life Sciences Fellow grant, Academy of Finland (grant numbers 314442, 311081, 335432, and 335436), and an investigator-initiated research grant from BMS.

Two different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): a randomised phase 3 trial.

BACKGROUND: Adjuvant high-dose interferon alfa-2b improves relapse-free survival (RFS) in patients with high-risk melanoma, although benefits in overall survival are uncertain. Because of the toxic effects of high-dose regimens, intermediate doses are being explored. We investigated whether adjuvant therapy with intermediate-dose interferon alfa-2b for 1 or 2 years would improve outcomes in patients with stage IIB-IIC or III resected cutaneous melanoma. METHODS: This randomised, open-label, phase 3, parallel-group trial was undertaken between 1996 and 2004. 855 patients were randomly assigned at 35 centres in the Nordic countries by block randomisation to three groups: observation only (group A); 4 weeks of induction (interferon alfa-2b 10 million units flat dose subcutaneously 5 days per week) followed by 12 months of maintenance therapy (interferon alfa-2b 10 million units flat dose subcutaneously 3 days per week; group B); or 1 month of induction and 24 months of maintenance (group C). Neither investigators nor patients were masked to treatment assignment. Patients were stratified for country and tumour stage; patients with stage III disease were further stratified for presence of metastatic lymph nodes at primary diagnosis versus at relapse, palpable versus non-palpable lymph-node metastases, and number of metastatic lymph nodes. The primary endpoint was overall survival in the two interferon alfa-2b groups combined. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01259934. FINDINGS: 284 patients were assigned to group A, 285 to group B, and 286 to group C; all patients were analysed. The median follow-up time was 72·4 months (IQR 46·9-98·0). We recorded no significant improvement in overall survival in patients given interferon alfa-2b compared with observation: median overall survival was 56·1 months (IQR 22·3 to >120·0) in group A, 72·1 months (25·8 to >120) in group B, and 64·3 months (24·7 to >120) in group C (p=0·600). Hazard ratios (HR) for overall survival were 0·91 (95% CI 0·74-1·10; p=0·642) for groups B and C combined versus observation; 0·91 (0·72-1·14; p=0·652) for group B versus observation; and 0·91 (0·72-1·15; p=0·858) for group C versus observation. Median RFS was 23·2 months (IQR 5·6 to <120) in group A, 37·8 months (10·8 to >120) in group B, and 28·6 months (8·6 to >120) in group C (p=0·034). HRs for RFS were 0·80 (0·67-0·96; p=0·030) for groups B and C combined versus observation, 0·77 (0·63-0·96; p=0·034) for group B versus observation, and 0·83 (0·68-1·03; p=0·178) for group C versus observation. The most common grade 3 and 4 adverse events were fatigue (five in group A [1·8%], 28 in group B [9·8%], and 32 in group C [11·2%]), myalgia (three [1·1%], 15 [5·3%], 14 [4·9%], respectively), and thrombocytopenia (15 [5·3%], 23 [8·1%], eight [2·8%], respectively). INTERPRETATION: Adjuvant therapy with intermediate-dose interferon alfa-2b did not significantly improve overall survival. Interferon alfa-2b with 1-year maintenance therapy significantly improved RFS, but we recorded no significant effect for 2-year maintenance therapy. Further research is in progress to define the subgroup of patients who benefit from adjuvant interferon alfa-2b. FUNDING: Schering-Plough (now Merck); the Radiumhemmet Research Funds, Stockholm; the Stockholm County Council; and the Swedish Cancer Society.