Adjuvant Therapy of Skin Melanoma With Alpha Interferon and Naderin

Protocol of Clinical Trial of EAFO 2012: Adjuvant Therapy of Skin Melanoma With Use of Alpha Interferon and Naderin

The goal of this clinical trial is to learn if adding alpha interferon to standard treatment works to prevent skin melanoma from coming back after surgery. The study will also learn if different doses of alpha interferon work better than others.

The main questions it aims to answer are:

• Does alpha interferon help people with melanoma live longer without the cancer returning?
• Does a higher dose of alpha interferon work better than a lower dose?
• How does alpha interferon affect the immune system? Researchers will compare six different treatment approaches to see which one works best.

Participants will:

• Have surgery to remove their melanoma
• Receive one of six different treatments after surgery:
• Radiation therapy (40 Gy)
• Low-dose interferon (3 million IU)
• Surgery alone (no additional treatment)
• High-dose interferon (9 million IU/m² IV)
• Low-dose interferon with chemotherapy (dacarbazine + cisplatin)
• Chemotherapy alone (dacarbazine + cisplatin)
• Have regular check-ups to see if the cancer returns
• Have blood tests to check immune system function Key finding: The study will determine which treatment approach provides the best chance of survival without cancer recurrence.

Study Rationale Cutaneous melanoma has a clinically meaningful risk of recurrence after complete surgical resection, particularly in higher-risk disease. Interferon alfa has historically been investigated as adjuvant immunotherapy in melanoma; randomized trials and meta-analyses have shown modest improvements in relapse-related endpoints with clinically important toxicity, and no consistent evidence that higher-dose strategies provide greater benefit than lower-dose strategies.

This study compared multiple adjuvant approaches used in local practice, including differing interferon dose intensities and combinations with cytotoxic chemotherapy or radiotherapy, to explore their comparative associations with recurrence and survival outcomes.

Study Design and Setting This was a single-country, comparative interventional study conducted after definitive surgery for cutaneous melanoma. Participants were allocated to one of six post-operative management groups based on clinical factors and treatment availability (non-randomized, open-label assignment).

Interventions (post-operative groups)

After surgical resection, participants received one of the following:

Adjuvant radiotherapy to the surgical bed: total dose 40 Gy.

Low-dose interferon alfa: 3 million IU subcutaneously on a scheduled regimen.

Observation / surgery alone (no adjuvant therapy).

Higher-dose interferon alfa: 9 million IU/m² intravenously on a scheduled regimen.

Low-dose interferon alfa + polychemotherapy: dacarbazine + cisplatin.

Polychemotherapy alone: dacarbazine + cisplatin. (Administration schedules, cycle lengths, and duration should be specified in the protocol or an accessible supporting document, consistent with protocol reporting standards.)

Assessments and Follow-up

Participants underwent baseline clinical evaluation after surgery and were followed at prespecified intervals for:

Disease status/recurrence surveillance (clinical assessments and imaging per local standard schedule).

Safety monitoring including treatment-emergent adverse events.

Immune monitoring via peripheral blood sampling with lymphocyte subset evaluation (including CD4/CD8 ratio) at baseline and predefined follow-up timepoints.

Outcomes (high-level; avoid duplicating Outcome Measures section) The study evaluated time-to-event and proportion-based clinical outcomes (recurrence and survival endpoints), safety/tolerability of each adjuvant approach, and longitudinal changes in immune markers.

Statistical Considerations (high-level) Time-to-event outcomes were planned for analysis using Kaplan-Meier methods with between-group comparisons using log-rank testing. Immune marker changes were planned for within- and between-group comparisons using parametric or nonparametric methods depending on distributional assumptions. A two-sided significance threshold of p < 0.05 was prespecified.

Limitations (protocol-relevant, non-results) Because treatment assignment was non-randomized, comparative estimates between groups are vulnerable to confounding by indication and selection bias. Interpretation of between-group differences therefore requires caution and may require adjustment methods (e.g., multivariable models/propensity approaches) if covariates were collected and sample size permits.

Inclusion Criteria:

• • Histologically confirmed diagnosis of skin melanoma (stages I-IV according to TNM classification)

  • Underwent complete surgical resection of primary tumor with negative margins
  • Age 18 years or older
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Life expectancy of at least 6 months
  • Adequate bone marrow function: absolute neutrophil count ≥ 1.5 × 10⁹/L, platelet count ≥ 100 × 10⁹/L, hemoglobin ≥ 90 g/L
  • Adequate hepatic function: bilirubin ≤ 1.5 × upper limit of normal (ULN), transaminases ≤ 2.5 × ULN
  • Adequate renal function: creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min
  • Willing and able to provide written informed consent
  • Willing to comply with study procedures and follow-up schedule

Exclusion Criteria:

• • Presence of distant metastases at the time of diagnosis (except for stage IV patients included per protocol)

  • Prior immunotherapy, chemotherapy, or radiotherapy for melanoma
  • History of other malignant neoplasms within the past 5 years (except non-melanoma skin cancer or carcinoma in situ of the cervix)
  • Severe or uncontrolled organ dysfunction (cardiac, hepatic, renal, pulmonary)
  • Active infection requiring systemic therapy
  • Known hypersensitivity to interferon-alpha or any study medications
  • Known hypersensitivity to dacarbazine, cisplatin, or any excipients
  • Pregnancy or breastfeeding
  • Psychiatric or cognitive impairment that would interfere with study participation
  • Participation in another interventional clinical trial within 30 days prior to enrollment
  • Any condition that, in the investigator's opinion, would compromise participant safety or interfere with study objectives