Malignant melanoma is a tumor of melanocytes in the skin 1. Malignant melanoma rarely occurs (only 4%) in skin cancer 2. Among all dermatologic cancers, 80% of cases are lethal 3. Research prospectus and clinical efforts in the prognosis of advancement of the stage of malignant melanoma are poor. Its prognosis in Chinese patients is high (20 000 new cases/year) 4. Therefore, the therapeutic management of malignant melanoma needs to be addressed soon as there are a large number of patients affected in People’s Republic of China.
Interferon-α (IFN-α) is mainly produced endogenously by macrophages and has proved anticancer effects in the experimental studies and the clinical trials 5. It has improved overall survival and disease-free survival in patients with high-risk cutaneous melanoma 6, but the mechanism of action is unclear yet 7. Treatment-emergent adverse effects are increased and cause a financial burden on patients when it is used with a chemotherapeutic agent(s) 6.
Interleukin-2 (IL-2) has complex biological effects and exerts an antitumor effect by enhancing cytotoxic T lymphocyte and natural killer cell lysis. Intravenously infused high dose of IL-2 (100–150×106 IU/m2/day) is more toxic than low dose (106 IU/m2/day) 4,8. Subcutaneous administration of IL-2 is less toxic than intravenous infusion 4. Continuous infusion is more toxic than continuous dripping 4 and has capillary leak syndrome and flu-like symptoms as adverse effects 4. However, it has higher efficacy for Chinese patients than US patients because Chinese patients get long response duration than White patients because of changes in its pharmacokinetics in different populations 9.
Although the US Food and Drug Association has approved IFN-α and IL-2 as adjuvant therapy in malignant melanoma 4,10. These forms of treatment have no guidelines associated with them in China, and the rationale for carrying out the study is to shed more light on the requirements of their inclusion.
The primary aim of the study was to treat Chinese patients with malignant melanoma using a high dose of subcutaneous IFN-α or continuous intravenous IL-2 for 4 months. The secondary end point of the trial was to compare the efficacy and safety of IFN-α therapy with IL-2 therapy and to do the research that Chinese guidelines are inadequate when it comes to using of IFN-α as a cancer treatment.
Patients and methods
IFN-α and IL-2 were purchased from Essex Pharma GmbH (Munich, Germany).
Compliance with ethical standards
The study had been registered in the Research registry (http://www.researchregistry.com), UID No. researchregistry4361, dated 9 January 2015. The protocol of the study (CMU/CL/03/15 dated 7 January 2015) had been approved by the Cancer Hospital of China Medical University Review Board. The study had adhered to the law of China, consolidated standards of reporting trials (CONSORT) 11, and Declaration of Helsinki (V2008) 12. An informed consent form with regard to interventions, pathology, and publications of the study including personal data and images in all formats (hard and/or electronic) irrespective to time and language had been signed by patients and their relatives (legally authorized persons).
All patients age 18 years and above with histologically confirmed and unresectable malignant melanoma, admitted to the Cancer Hospital of China Medical University (Shenyang, China), and the referring hospitals from 13 January 2015 to 1 December 2017 were included in the trial. Patients with Eastern Cooperative Oncology Group performance status (0–5 scale, with regard to disease progression, where 0: fully active patient and 5: dead 13) score of 2 or less were included in the study. Patients who had adequate functioning of vital organs (kidney, heart, brain, lungs, and liver) were included in the trial. The demographic parameters of the enrolled patients are presented in Table 1.
Patients who have received steroids and had forced expiratory volume less than 75% were excluded from the study. Patients who had not signed an informed consent form were also excluded from the trial.
Design of experiment
A total of 250 patients were subjected to simple randomization (1 : 1 ratio). All the patients have been treated identically before the trial. Prefilled envelopes were used for the purpose of randomization. The physicians involved in the randomization were not involved in the treatment. The sample size was calculated using OpenEpi 3.01-English (Open Source Epidemiologic Statistics for Public Health, Los Angeles, USA). The sample size was found to be 125 for both groups. The other factors, two-sided confidence intervals were 80%, the outcome in both groups was 95% (α=0.05), the risk ratio detected was 1, and the normal approximation was 9.917%. The flow diagram of the study is presented in Fig. 1.
As first-line therapy, patients of IFN-α group received subcutaneous 9×106 IU/m2 IFN-α at every 21 days for 4 months 1. Patients of IL-2 group received continuous (over 96 h) intravenous 9×106 IU/m2 IL-2 at every 21 days for 4 months 14.
The Response Evaluation Criteria in Solid Tumors v1.1 guideline was used for evaluation of disease progression and tumor response 15. The computed tomography of the pelvis, abdomen, and the chest and MRI of the brain were used to assess the treatment response. Times to tumor progression were considered from the time of intervention initiation to proof of tumor progression. Overall survival was considered from the time of detection of malignant melanoma to the death 14.
Treatment-emergent adverse effects
The US National Cancer Institute’s Common Terminology Criteria for Adverse Events v4.0 were used for evaluation of toxicity 16. Patients subjected to an anatomical characterization and laboratory tests. Lactate dehydrogenase (lactate dehydrogenase test), complete metabolic panel (blood and urine glucose level, blood sodium, blood potassium, blood carbon dioxide, blood chloride levels, and liver function test), and complete blood count (red blood cell count, hemoglobin, white blood cell count, and platelet count) during and before every cycle were evaluated 14.
Cost of treatment
The purpose of calculating the cost in the study was to check the need for financial help for treatment to patients or not. Cost of treatment was included in the cost of diagnosis, interventions, healthcare management, and expert charges. The cost was considered from the time of detection of malignant melanoma to the death.
InStat (version Window; GraphPad, Indiana, San Diego, California, USA) was used for statistical analysis. Repeated measures analysis of variance was used for continuous data and the χ2-independence test was used for constant data. Results were considered significant at 95% of confidence level. Intention-to-treat method of analysis was adopted.
Radiographic images concluded that after 4 months, patients of both groups had an absence of brain, lung, heart, and liver metastases in the patients who had no brain, lung, heart, and liver metastases before treatment. Even if brain metastasis was present at the time of enrollment (Fig. 2a), IL-2 was effective to improve brain metastasis after 4 months of intervention (Fig. 2b). However, IFN-α failed to improved metastasis after 4 months of intervention.
Compared with before treatment (Fig. 3a), IL-2 was effective in improving malignant melanoma after 4 months of intervention (Fig. 3b). In a similar manner, as compared with before treatment (Fig. 4a) IFN-α was also effective in improving malignant melanoma after 4 months of intervention (Fig. 4b).
The overall survival was counted up to 800 days of the follow-up period, and progression-free survival was counted up to 500 days of the follow-up period. Patients of the IL-2 group had a higher overall survival (P<0.0001; Fig. 5) and a higher progression-free survival (P=0.002; Fig. 6) than those of IFN-α group.
Hypotension, kidney dysfunction, and liver dysfunctions were major continuous intravenous IL-2-emergent adverse effects. Thrombocytopenia and neutropenia were major subcutaneous IFN-α-emergent adverse effects (Table 2).
Continuous intravenous IL-2 caused flu-like symptoms (chills, muscle pain, and fever) and capillary leak syndrome (systemic edema, pulmonary edema, weight gain, ascites, and pleural effusion; Table 3).
Healthcare management and expert charges lead to increase in the cost of treatment for IL-2 group than IFN-α group (total cost of therapy: 105 345±9845 ¥/patient vs. 95 656±7586 ¥/patient, P<0.0001; Fig. 7).
In the study, subcutaneous IFN-α or continuous (dripping over 96 h) intravenous IL-2 as a first-line therapy in patients with malignant melanoma was preferred instead of using a chemotherapeutic agent(s). The chemotherapeutic agents used in malignant melanoma like cisplatin induce thrombocytopenia, acute renal failure, and peripheral neuropathy 14. Vinca alkaloids and nab-paclitaxel induce neurotoxicity and neutropenia 17. Docetaxel and carboplatin have adverse effects like neutropenia, anemia, and thrombocytopenia 18. Fresolimumab may develop hyperkeratosis 19 and squamous cell carcinomas 20. Moreover, combination therapies of chemotherapeutic agent(s) with IFN-α or IL-2 may have somewhat higher tumor response but have severe toxicities and the less overall survival of the patients 17. IFN-α has immunoregulatory, antiangiogenic, antiproliferative, differentiation-inducing, and proapoptotic effects 21. IL-2 is a natural part of the immune system. It is a messenger molecule (cytokine) that is secreted from specific cells to alert other cells about an infection. 106 IU/m2/day (low dose) of IL-2 is not effective and its high dose (100–150×106 IU/m2/day) is toxic 8. 700×106 IU/m2/week subcutaneous administration of IL-2 is less toxic than 100×106 IU/m2/day intravenous infusion but more toxic than 9×106 IU/m2/3-week dripping over 96 h 4. Overall survival irrespective of disease conditions is higher for patients who received subcutaneous IFN-α than those who received the same dose of continuous IFN-α 22. With respect to the regimen selected in the study for patients, the researchers justified interventions to improve overall survival and quality of life with or without disease activity of patients.
The trial was performed with IL-2 and IFN-α for six cycles only at the interval of 21 days. Previous studies have reported that administration of IFN-α for short period (4 weeks) and long period (1 year) has the same relapse-free survival in White patients 1,23 and administration of IL-2 for a longer period of time is not tolerated by patients 4,24. With respect to interventions of the subjects, the trial was designed so that they achieve maximum response with minimum toxicities.
After 4 months, patients of both groups had an absence of brain, lung, heart and liver metastases. However, kidney and liver dysfunctions and hypotension were reported in the patients who had received continuous intravenous IL-2. IL-2 has cardiovascular toxicities 9. Continuous intravenous IL-2 has urogenital and hepatic adverse effects 4,25. Even patients of the IL-2 group had flu-like symptoms and capillary leak syndrome as measured by nonhematological adverse effects. Hypovolemia owing to capillary leak syndrome may reduce blood perfusion in the brain, resulting in dysfunction of the body 4. However, low dose of IFN-α (intravenous 10×106 IU/m2) has only flu-like symptoms, nausea, and nonhematological adverse effects 26. In considering the adverse effects of the study, subcutaneous IFN-α is the reasonable treatment option for patients with malignant melanoma but Chinese guidelines for treatment of malignant melanoma has not recommended low and medium doses of subcutaneous IFN-α because it does not improve the survival, and there is no experience of using higher subcutaneous dose (10×106 IU/m2/3 weeks) of IFN-α in Chinese patients 4. Therefore, Chinese guidelines for treatment of malignant melanoma are required to update in terms of adjuvant treatment of malignant melanoma.
The treatment with subcutaneous IFN-α was cheaper than continuous intravenous IL-2 but had less overall survival and less progress-free survival. Subcutaneous IFN-α has no significant effects as compared with placebo 4,27,28 but has better response in ulcerated primary melanoma 29. Subcutaneous IFN-α could be recommended in relapse-free patients.
There were several limitations of the study, for examples, the results of the study were applicable to Chinese patients only. The effects of demographic characteristics on the response were not evaluated. Measures used to control adverse effects were not discussed. The effects of measures to maintain toxic effects on overall survival and quality of life of patients were not discussed. The blinded procedure has more reliable results, but in the study, blinding was not possible. The change in immune cells and other cell types and their effect/role in disease progression and tumor response were not examined.
Subcutaneous IFN-α is a safer option than continuous intravenous IL-2 in patients with malignant melanoma. However, the good response may be reported in continuous intravenous IL-2 in short treatment period with moderate adverse effects.
Authors are thankful for the medical, pathological, radiological, and other nonmedical staff of Cancer Hospital of China Medical University, Shenyang, China; Ross University School of Medicine, Miramar, Florida, USA; and the Graduate School, China Medical University, Shenyang, China.
The funding for the treatment was done by the patients themselves.
Authors’ contributions: All contributing authors listed on the manuscript are aware of and agree to the submission of this manuscript. S.L. and X.W. equally contributed to the conceptualization, the design, and formal analysis of the study. P.C. was the project administrator and contributed to visualization and the design of the study. Y.P. contributed to the conceptualization, data curation, supervision, and validation of the study. K.Z. contributed to the design, resources, and investigation for the study. W.W. contributed to the methodology, resources, and software for the study. E.Q. contributed to the conceptualization, data curation, formal analysis, and supervision of the study. X.Z. contributed to the conceptualization, data curation, and the draft and edited the manuscript for intellectual content. The authors agree to be accountable for all aspects of work ensuring integrity and accuracy.
Availability of data and materials: The datasets used and analyzed during the current study were available from the corresponding authors on reasonable request.
Conflicts of interest
There are no conflicts of interest.
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
brain metastasis; interferon-α; interleukin-2; malignant melanoma; melanocytic tumor; thrombocytopenia