Melanoma Stage I, Melanoma Stage II, Melanoma Stage III, Skin Melanoma
Conditions
Keywords
Melanoma, Alpha Interferon, Immunotherapy, Adjuvant Therapy, CD4/CD8 Ratio, Recurrence-Free Survival, Overall Survival
Brief summary
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.
Detailed description
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.
Interventions
PROCEDURESurgical resection
Wide excision of primary skin melanoma under general intravenous anesthesia. Incision margin: 4-5 cm from visible tumor edge on trunk, 3 cm on head and neck, excised as a single block with subcutaneous fat and superficial fascia. For lower extremity melanoma in 7 patients, wide excision performed without skin closure (open wound management). Regional lymphadenectomy (Duke's operation for inguinal area or axillary lymphadenectomy) performed if enlarged regional lymph nodes present or for Clark invasion level III-IV
RADIATIONAdjuvant Radiotherapy
External beam gamma radiotherapy delivered to primary melanoma site and regional lymph node area. Regimen: 2 Gray (Gy) per fraction daily. Total dose: 40 Gy to primary tumor site, 20 Gy to regional lymph node area. Indicated only for localized melanoma with Clark invasion level I-II (T1-2N0M0). Not recommended for deeper invasion (T3-4N0M0) as it may accelerate disease progression
BIOLOGICALinterferon alfa
Recombinant interferon alfa (IFN-α) immunotherapy administered in two dosing regimens. Low-dose regimen: 3 million IU intradermal daily until cumulative 30 million IU, then maintenance 3 million IU single dose only when CD4/CD8 ratio \<1.3. High-dose regimen: 9 million IU/m² intravenous every 2 days for 4 total doses. High-dose regimen associated with severe adverse events (fever 39-40°C, headache, nausea, cardiotoxicity, hepatotoxicity, nephrotoxicity, leukopenia) leading to treatment discontinuation in 29.6% of patients.
Alkylating agent chemotherapy. Administered intravenously at 1400 mg per cycle. Used in combination with cisplatin for adjuvant polychemotherapy. Cycle repeats every 21 days for total of 6 cycles. Common adverse effects: nausea, vomiting, stomatitis, alopecia, short-term diarrhea.
DRUGCisplatin
Platinum-based chemotherapy agent. Administered intravenously at 50 mg per cycle. Used in combination with dacarbazine for adjuvant polychemotherapy. Cycle repeats every 21 days for total of 6 cycles. Adverse effects: nausea, vomiting, nephrotoxicity (managed with hydration), ototoxicity
DIAGNOSTIC_TESTImmunological Monitoring
Monitoring of cellular immunity parameters including CD3, CD4, CD8, and CD4/CD8 ratio (immune regulatory index) using monoclonal antibodies. Performed at baseline pre-surgery, then at 1 month post-surgery, every 2 months for first year, and every 3 months for subsequent 5 years. CD4/CD8 ratio \<1.3 indicates immunosuppression requiring intervention. Ratio decline over 3-6 months predicts disease recurrence in 98.2% of cases.
DIAGNOSTIC_TESTSkinscope Dermatoscopy
Non-invasive dermatoscopy device (Menard, Japan) for detecting subclinical intradermal satellite metastases in melanoma patients. Provides 40-80x magnification with surface and deep imaging modes. Enables photo/video capture and analysis. Sensitivity: 75.0±4.1% for detecting intradermal metastases vs. 26.0±3.4% with visual examination alone. Helps determine appropriate surgical margins. Priority certificate No.2009/1105.1 dated 04.09.2009.
Sponsors
MIPO Clinic
Asfendiyarov Kazakh National Medical University
Kazakh Research Institute of Oncology & Radiology
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
This is an open-label study. Participants, care providers, and investigators are aware of the treatment assignments. However, the outcomes assessor performing the survival analysis and CD4/CD8 ratio measurements is blinded to treatment allocation to reduce bias in outcome assessment.
Intervention model description
Six parallel treatment groups based on TNM stage and risk category. Groups I-III (localized melanoma, n=151): surgery+radiotherapy (49), surgery+low-dose IFN-α (38), surgery alone (64). Groups IV-VI (locoregional melanoma, n=127): surgery+high-dose IFN-α (37), surgery+low-dose IFN-α+polychemotherapy (47), surgery+polychemotherapy alone (43). Non-randomized allocation.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence-free survival | Up to 5 years following surgical resection | Time from surgical resection to first documented recurrence of melanoma (local, regional, or distant) or death from any cause, whichever occurs first. Assessed through clinical examination, imaging studies, and histopathological confirmation when applicable. |
| 5-year overall survival | 5 years following surgical resection | Proportion of participants alive at 5 years following surgical resection. Survival status assessed through clinical follow-up visits and medical records review. |
| Change in CD4/CD8 Ratio | Baseline and at 6 months post-treatment | Change in the ratio of CD4-positive to CD8-positive T lymphocytes from baseline to post-treatment. Measured by flow cytometry using peripheral blood samples. Assesses immunologic response to interferon-alpha therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of treatment-related adverse events | Through treatment completion, up to 12 months | Proportion of participants experiencing treatment-related adverse events, including severity grading according to Common Terminology Criteria for Adverse Events (CTCAE). Particular focus on toxicity leading to treatment discontinuation. |
| Time to recurrence | Up to 5 years following surgical resection | Time from surgical resection to first documented recurrence of melanoma, measured in months. Participants without recurrence are censored at the date of last follow-up. |
| Disease-free survival | Up to 5 years following surgical resection | Time from surgical resection to first recurrence, second primary melanoma, or death from any cause, whichever occurs first. |
Outcome results
None listed