isotretinoin and Melanoma

Combining chemotherapy and immunotherapeutic agents such as interleukin-2 and interferon alpha-2b might improve treatment results in metastatic melanoma (MM) patients compared with chemotherapy alone. This prospective study evaluated the potential efficacy of a biochemotherapy regimen followed by maintenance biotherapy for the treatment of MM. Twenty-two patients with stage IV melanoma were treated for 5 consecutive days with cisplatin at 20 mg/m, vinblastine at 1.6 mg/m, and dacarbazine at 160 mg/m. Pegylated interferon alpha-2b at a dose of 50 microg every week, subcutaneous interleukin-2, 1.8 MIU, and oral 13-cis-retinoic acid (13-cis-RA) at 0.5 mg/kg were given 5 days/week for 3 weeks each month during the period of chemotherapy administration. Maintenance biotherapy was continued in patients who had a complete or partial response or disease stability (clinical benefit) after six courses of biochemotherapy. The primary endpoint was response; secondary endpoints were the evaluation of the immunologic parameters, toxicity, progression-free survival, and overall survival. Twelve patients (54.5%) achieved a response, and seven (31.8%) maintained stable disease for at least 6 months with maintenance biotherapy. The median progression-free survival and overall survival were 23.3 and 45.7 months, respectively. The most important toxicities from chemotherapy were grades 3 and 4 neutropenia and thrombocytopenia in 41 and 18% of patients, respectively, whereas grade 2 autoimmune reactions were observed in 21% of patients after maintenance biotherapy. A prolonged enhancement of immunologic function was observed in the 19 patients treated with maintenance therapy. A regimen of six cycles of biochemotherapy followed by maintenance immunotherapy is well tolerated, and shows significant activity in patients with MM.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Dacarbazine; Dexamethasone; Diarrhea; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Therapy; Female; Humans; Immunotherapy; Interferon alpha-2; Interferon-alpha; Interleukin-2; Isotretinoin; Magnesium Sulfate; Male; Melanoma; Middle Aged; Neutropenia; Polyethylene Glycols; Prospective Studies; Recombinant Proteins; Treatment Outcome; Vinblastine

The combination of interferon alfa (IFNalpha) and isotretinoin has shown a direct antiproliferative effect on human melanoma cell lines, but it remained unclear whether this combination is more effective than IFNalpha alone in patients with metastatic melanoma. We evaluated safety and efficacy of IFNalpha and isotretinoin compared with IFNalpha alone as adjuvant treatment in patients with primary malignant melanoma stage IIA and IIB.. In a prospective, randomized, double-blind, placebo-controlled trial, 407 melanoma patients in stage IIA (301 patients) and IIB (106 patients) were randomly assigned to either IFNalpha and isotretinoin (isotretinoin group; 206 patients) or IFNalpha and placebo (placebo group; 201 patients) after excision of the primary tumor. IFNalpha was administered three times a week at a dose of 3 million units subcutaneously for 24 months. Isotretinoin at a dose of 20 mg for patients < or = 73 kg, 30 mg for patients greater than 73 kg, or placebo daily for 24 months.. A scheduled interim analysis revealed no significant differences in survival rates, with the isotretinoin group and the placebo group showing 5-year disease-free survival rates of 55% (95% CI, 46% to 65%) and 67% (95% CI, 59% to 75%), respectively, and overall 5-year survival rates of 76% (95% CI, 67% to 84%) and 81% (95% CI, 74% to 88%), respectively. The trial was stopped for futility.. The addition of isotretinoin to an adjuvant treatment of low-dose IFNalpha in patients with stage IIA and IIB melanoma had no significant effect on disease-free or overall survival and is therefore not recommended.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Disease-Free Survival; Double-Blind Method; Europe; Female; Head and Neck Neoplasms; Humans; Hyperlipidemias; Interferon-alpha; Isotretinoin; Male; Melanoma; Middle Aged; Multivariate Analysis; Neoplasm Staging; Prognosis; Prospective Studies; Quality of Life; Skin Diseases; Treatment Outcome

To analyze whether an abnormal retinal function in patients with a cutaneous malignant melanoma was due to paraneoplastic retinopathy or due to isotretinoin or interferon-alpha.. We studied 15 patients with malignant melanoma in stage IIa and IIb who are all participants in a randomized, multicentered, double-blind placebo-controlled clinical trial comparing interferon-alpha/isotretinoin versus interferon-alpha/placebo performed by the Department of Dermatology, University of Graz. Our assessment included a full ophthalmic history and examination, electrophysiological testing (ERG, EOG), dark adaption, color vision and visual field testing.. The most prevalent ocular symptom patients complained about was ocular dryness (8 patients). Electrophysiological as well as psychophysical testings showed no abnormalities in 12 patients. In 1 patient the therapy was stopped because of electrophysiological and psychophysiological pathology. This patient suffered from severe reduction of night vision and visual disturbances. Another patient had had night blindness since childhood which remained stable.. We postulate that in 1 of 15 patients, visual complaints are caused with a high probability by melanoma-associated retinopathy although, in the literature, isotretinoin is described to show similar effects on retinal function.

Topics: Aged; Antineoplastic Agents; Color Perception; Double-Blind Method; Drug Therapy, Combination; Electroretinography; Female; Humans; Interferon-alpha; Isotretinoin; Male; Melanoma; Night Blindness; Paraneoplastic Syndromes; Prognosis; Retinal Diseases; Skin Neoplasms; Visual Acuity; Visual Fields

Treatment for metastatic melanoma is limited by low response rates to single- or combination-agent chemotherapy. Recent studies have examined the role of biologic modifiers and differentiating agents. This phase II study examined the efficacy and toxicity of combining alpha-2b-interferon (IFN alpha) and 13 cis retinoic acid (cRA) in the treatment of metastatic malignant melanoma. Thirteen patients were treated with IFN alpha (5 x 10(6) units/m2 three times weekly) and cRA (1 mg/kg per day). One patient with lung and adrenal metastases had a partial response 6 months in duration and two patients had stabilization of lung metastases for 2 months. All other patients had progressive disease. Toxicity was substantial with all patients experiencing Eastern Cooperative Oncology Group grade 1-2 fatigue, myalgias, anorexia, stomatitis, and cheilitis. In addition, serum cholesterol and triglycerides were elevated in all patients. Seven patients required 50% dose reductions because of hypertriglyceridemia, fatigue associated with a significant decline in performance status, and severe stomatitis with anorexia and weight loss. One patient discontinued therapy because of a decline in performance status. This study suggests this combination of cRA and IFN alpha is inactive in the treatment of metastatic melanoma and is associated with substantial toxicity.

Topics: Adult; Antineoplastic Agents; Drug Therapy, Combination; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Keratolytic Agents; Male; Melanoma; Middle Aged; Recombinant Proteins

The pharmacokinetics of 13-cis-retinoic acid (13cisRA) and its effects on retinol plasma levels were investigated after the first and the last doses in melanoma patients, who participated in a study run to assess tolerance over a long period of a treatment schedule of 13cisRA associated with recombinant interferon alpha2a (rIFN-alpha2a). Melanoma patients with regional node metastases after radical surgery were randomized to be treated for 3 months with rIFN-alpha2a, 3 x 10(6) IU s.c. every other day, associated with oral 13cisRA at doses of 20 mg day(-1) (five patients) or 40 mg every other day (seven patients). Maximum 13cisRA blood concentrations usually occurred 4 h after drug administration, with average values of 406 and 633 ng ml(-1) (i.e. 1.3 and 2.1 microM) after the 20 and 40 mg dose respectively. The average half-life (t(1/2)) was approximately 30 h. The maximum concentration, the t(1/2) and the area under the concentration-time curves from 0 to 48 h (AUC(0-48)) of 13cisRA did not change after multiple dosing, whereas the AUC(0-48) of its major blood metabolite, 4-oxo-13-cis-retinoic acid, increased. Immediately after 13cisRA treatment, retinol plasma levels started to decline and they reached the lowest values (approximately 20% reduction) shortly after the time of maximum 13cisRA concentrations (i.e. 4-12 h after drug intake). Afterwards, values returned to baseline. The amount of retinol reduction in time was correlated with 13cisRA maximum concentrations.

Topics: Adult; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Male; Melanoma; Middle Aged; Recombinant Proteins; Vitamin A

Twenty-five patients with metastatic malignant melanoma were treated with isotretinoin (13-cis-retinoic acid) orally at 1 mg/kg daily and recombinant interferon alfa-2a (INF-alpha) subcutaneously at 3 million units daily for 16-48 weeks. Therapy was well tolerated; fatigue and hyperlipidemia were the most frequent dose-limiting toxicity and necessitated dose reductions in 14 patients. Two patients achieved a complete response, and 3 responded partially for a total response rate of 20% (95% confidence interval: 4-36%). Responses occurred primarily in patients with limited tumor burden and disease confined to the skin and lymph nodes. Significant elevations in peripheral blood 2'-5'-oligoadenylate synthetase activity and natural killer activity were observed with therapy. The magnitude of these changes, however, was not predictive of response. Biopsy specimens of two responding lesions showed extensive necrosis of tumor. One specimen showed large aggregates of melanophages in association with tumor. The combination of isotretinoin and IFN-alpha is an active, easily administered regimen with acceptable toxicity for metastatic malignant melanoma.

Topics: 2',5'-Oligoadenylate Synthetase; Adult; Aged; Antineoplastic Agents; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Killer Cells, Natural; Lymph Nodes; Lymphatic Metastasis; Male; Melanoma; Middle Aged; Necrosis; Neoplasm Metastasis; Neoplasm Staging; Recombinant Proteins; Skin Neoplasms

The effect of 13-cis-retinoic acid and highly purified human leukocyte interferon alpha (Alphaferon) therapy for metastatic melanoma was studied. A group of 17 patients with disseminated malignant melanoma were treated over a 6-month period. They received 60 mg 13-cis-retinoic acid/day continuously and ten cycles of interferon alpha (IFN alpha). IFN was administered by subcutaneous injection, at a daily dose of 6 x 10(6) IU Alphaferon. The 5-day treatment period was followed by an IFN-free interval of 2 weeks. We were able to observe an overall response rate of 30% with 12% complete responses (2 out of 17 patients). Sites of response included the skin, lung, liver and lymph nodes. All responses have now lasted over 6 months. Therapy was generally well tolerated and could be performed on an outpatient basis. Side-effects of this combination therapy did not exceed the established side-effects of the two substances. We also studied 2'-5'-oligoadenylate synthetase, beta 2-microglobulin and neopterin levels during the whole treatment course. All patients were within the normal range before treatment and a sharp rise occurred during each IFN cycle. The maximum being observed 24 h after the third injection. This indicates a high biological activity of IFN alpha administered cyclically during the whole treatment course. This finding also corresponds well with the absence of neutralizing antibodies before and after the whole treatment period.

Topics: 2',5'-Oligoadenylate Synthetase; Adolescent; Adult; Aged; beta 2-Microglobulin; Biopterins; Chemotherapy, Adjuvant; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Interferon-alpha; Isotretinoin; Male; Melanoma; Middle Aged; Neopterin; Remission Induction; Treatment Outcome

The combination of alpha-interferon and 13-cis-retinoic acid has shown significant activity against a number of human tumors. We conducted a phase II trial to test whether the combination would have a major response rate of 30% or more in patients with refractory, metastatic melanoma. Eleven patients were treated on the study. Alpha-interferon was administered subcutaneously three times a week at a dose of 10 million U/m2 and 13-cis-retinoic acid was administered orally at a dose of 1 mg/kg/day. No patient achieved a partial or complete remission. The combination of alpha-interferon and 13-cis-retinoic acid is unlikely to have significantly higher therapeutic activity than alpha-interferon alone.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Interferon-alpha; Isotretinoin; Male; Melanoma; Middle Aged

Vemurafenib, a kinase inhibitor that targets tumors with the BRAF V600E mutation, is a promising option for unresectable or metastatic melanoma. Cutaneous side-effects have been reported including alopecia, photosensitivity, squamous cell carcinoma, keratoacanthomas, keratosis pilaris-like eruption, and palmoplantar hyperkeratosis. Acneiform eruptions have been reported in 3%-6% of the patients treated with BRAF inhibitors,and 5 cases are described in the literature. Although they responded well to topical therapies, oral antibiotics, or observation, one case required oral etretinate and the withdrawal of vemurafenib because the adverse event reached grade 3. We report one case of a severe acneiform eruption associated with vemurafenib with a good response to isotretinoin allowing continuation of the BRAF inhibitor.

Topics: Acneiform Eruptions; Adult; Antineoplastic Agents; Dermatologic Agents; Drug Eruptions; Female; Humans; Isotretinoin; Melanoma; Severity of Illness Index; Skin Neoplasms; Vemurafenib

Resistance to chemotherapy is a major hurdle in the treatment of malignant melanoma. Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in different tumor types, including melanoma, and to reverse epigenetic repression of tumor suppressor genes, such as retinoic acid receptor beta (RARbeta). In this study, we tested the antitumor effect of the HDAC inhibitor LAQ824 in combination with 13-cis-retinoic acid (CRA) on two human melanoma cell lines both in vitro and in vivo. Treatment of LAQ824 showed a dose-dependent inhibitory effect on A2058 and HMV-I cell lines in a clonogenic assay. These cell lines were relatively resistance to CRA. On treatment with combination of LAQ824 and CRA, a greater inhibitory effect (up to 98%) was achieved compared with single agents. Lack of RARbeta2 gene expression was associated with histone acetylation and gene methylation at the promoter level. Treatment with LAQ824 restored retinoid sensitivity by reverting RARbeta2 epigenetic silencing. The biological effect of LAQ824 was associated with p21 induction in both cell lines but G(2) cell cycle arrest in A2058 and apoptosis in HMV-I cell line. The induction of apoptosis by LAQ824 was associated with increased reactive oxygen species and induction of SM22 gene expression in HMV-I but not in A2058 cell line. Administration of the free radical scavenger l-N-acetylcysteine blocked LAQ824 + CRA-mediated apoptosis in HMV-I cells, suggesting a primary role for reactive oxygen species generation in LAQ824 + CRA-associated lethality. Combination treatment showed 61% and 82% growth inhibition in A2058 and HMV-I tumors, respectively. Greater induction of in vivo apoptosis was observed in the HMV-I but not in the A2058 tumors treated with combination therapy compared with single agents. These results suggest that the HDAC inhibitor LAQ824 has a greater antitumor activity in combination with CRA in melanoma tumors but the degree of induced apoptosis may vary. Combination of HDAC inhibitors and retinoids represents a novel therapeutic approach for malignant melanoma that warrants clinical testing.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; G2 Phase; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Isotretinoin; Male; Melanoma; Mice; Mice, Nude; Microfilament Proteins; Muscle Proteins; Reactive Oxygen Species; Receptors, Retinoic Acid; RNA, Messenger

Topics: Apoptosis; Caspase 3; Caspases; Cell Line, Tumor; Cell Proliferation; Humans; Isotretinoin; Melanoma; Receptors, Retinoic Acid; Retinoid X Receptors; Tretinoin

Topics: Antineoplastic Agents; Chemotherapy, Adjuvant; Head and Neck Neoplasms; Humans; Interferon-alpha; Isotretinoin; Melanoma; Neoplasm Staging; Risk Factors; Treatment Outcome

We assessed the antiproliferative effects of human recombinant interferon-alpha2a (IFNalpha2a) and 13-cis-retinoic acid (13cis-RA) on two human melanoma cell lines (JR8 and M14). Both cell lines showed a very modest sensitivity to IFNalpha2a and 13cis-RA as single agents. In JR8 cells, the combination of the two compounds consistently produced simple additive effects. In contrast, different effects of the combination were recorded in the M14 cell line depending on the treatment schedule. Specifically, an additive interaction was observed when IFNalpha2a and 13cis-RA were given in sequence, independently of the order of drug administration, whereas a supra-additive antiproliferative effect was seen when cells were simultaneously exposed to the two drugs. Exposure to 1000 IU/ml IFNalpha2a markedly increased the nuclear expression of signal transducers and activators of transcription (STAT) proteins in both cell lines. By itself 10 microM 13cis-RA did not affect STAT protein expression or modify the extent of activation of such proteins by IFNalpha2a. Results from our study showed an enhancement of the antiproliferative activity of IFNalpha2a and 13cis-RA when given in combination and suggest that such an enhancement is not mediated by a concomitant effect of 13cis-RA on STAT protein activation.

Topics: Cell Count; Cell Cycle; Cell Division; DNA-Binding Proteins; Drug Combinations; Drug Synergism; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Melanoma; Recombinant Proteins; Signal Transduction; STAT1 Transcription Factor; STAT2 Transcription Factor; Trans-Activators; Tumor Cells, Cultured

Natural interferon alpha (nIFN-alpha) isotretinoin and their combination were tested for their capacity to modulate the proliferation of different human melanoma cell lines. Modulation of cell growth was measured using the MTT-assay. Isotretinoin and nIFN-alpha as single agents inhibited the proliferation in a dose dependent manner in the three cell lines: SK-Mel-30, SK-Mel-28 and MaRi. The combination of isotretinoin and nIFN-alpha led to a marked enhancement of the antiproliferative effect compared with either nIFN-alpha or isotretinoin alone in SK-Mel-30 cells. In contrast, there were no additive effects on growth inhibition of melanoma cell lines SK-Mel-28 and MaRi when nIFN-alpha and isotretinoin was combined. In one melanoma cell line (MaRi) proliferation was actually enhanced by isotretinoin in combination with nIFN-alpha. These results demonstrate the heterogeneous response of human melanoma cell lines to noncytotoxic concentrations of isotretinoin and nIFN-alpha alone and in combination.

Topics: Cell Division; Drug Synergism; Growth Inhibitors; Humans; Interferon-alpha; Isotretinoin; Melanoma; Tumor Cells, Cultured

The effect of a mixture of vitamins in modifying the efficacy of commonly used drugs in the treatment of human melanoma has not been studied. Vitamin C and d-alpha-tocopheryl succinate (alpha-TS) alone reduced the growth of human melanoma (SK-30) cells in culture, whereas beta-carotene (BC), 13-cis-retinoic acid (RA), or sodium selenite alone was ineffective. RA caused morphological changes, as evidenced by flattening of cells and formation of short cytoplasmic processes. A mixture of four vitamins (vitamin C, BC, alpha-TS, and RA) was more effective in reducing growth of human melanoma cells than a mixture of three vitamins. The growth-inhibitory effect of cis-platin, decarbazine, tamoxifen, and recombinant interferon-alpha 2b was enhanced by vitamin C alone, a mixture of three vitamins (BC, alpha-TS, and RA), and a mixture of four vitamins (vitamin C, BC, alpha-TS, and RA) that contained 50 micrograms/ml of vitamin C. These data show that a mixture of three or four vitamins can enhance the growth-inhibitory effect of currently used chemotherapeutic agents on human melanoma cells.

Topics: Ascorbic Acid; beta Carotene; Carotenoids; Cell Division; Cisplatin; Dacarbazine; Drug Screening Assays, Antitumor; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Melanoma; Recombinant Proteins; Tamoxifen; Tocopherols; Tumor Cells, Cultured; Vitamin E; Vitamins

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Congresses as Topic; Female; Head and Neck Neoplasms; Humans; Insurance, Pharmaceutical Services; Interferon-alpha; Isotretinoin; Medical Oncology; Melanoma; Ovarian Neoplasms; Societies, Medical; United States

13-cis retinoic acid has been shown to be a stereospecific suicide inhibitor of thioredoxin reductase purified from human melanoma tissue. All trans retinoic acid does not inhibit this enzyme. The covalent addition of 13-cis retinoic acid to the thiolate active site of thioredoxin reductase produces a thioether enzyme-inhibitor complex. This has been established by a kinetic analysis and by active site labeling with 3H-13 cis retinoic acid. A mechanism involving Michael addition of the thiolate group in the active site of thioredoxin reductase to the 13-cis double bond of enzyme-bound inhibitor has been proposed. This reaction may be important in the human epidermis because thioredoxin reductase has been shown to be a major antioxidant catalyst in human keratinocytes, melanocytes, melanoma cells, and in human skin as well as in melanoma tissues.

Topics: Cells, Cultured; Cytosol; Epidermis; Humans; Isotretinoin; Kinetics; Melanoma; NADH, NADPH Oxidoreductases; Skin Neoplasms; Stereoisomerism; Thioredoxin-Disulfide Reductase

We previously reported a favorable histologic response of dysplastic nevi to topical tretinoin in three patients. To investigate the anticancer and cancer preventive effects of retinoids we have examined the effect of systemic isotretinoin on dysplastic nevi. After confirmatory baseline biopsies, eleven patients with the dysplastic nevus syndrome were treated with oral isotretinoin, 40 mg twice a day for 4 months. At completion of therapy, at least three previously identified and photographed clinically typical dysplastic nevi were rephotographed and removed for histologic evaluation. Eight patients completed the full course of medication. There were no clinical changes in the dysplastic nevi in these patients. Posttherapy biopsy specimens in six volunteers revealed most of the remaining lesions to be dysplastic nevi. The majority of lesions biopsied in two subjects showed normal, benign nevi only. This proportion of clinically typical dysplastic nevi that prove to be normal nevi histologically (28%) is not significantly different from that reported by others. Oral isotretinoin does not appear to have a significant biologic effect on the clinical or histologic appearance of dysplastic nevi in the treatment schedule employed.

Topics: Administration, Oral; Adolescent; Adult; Aged; Biopsy; Dysplastic Nevus Syndrome; Female; Humans; Isotretinoin; Male; Melanoma; Middle Aged; Risk Factors; Skin Neoplasms

The effects of retinol, all-trans-retinoic acid, isotretinoin and etretinate on the activity of basement membrane collagen degrading enzyme was studied in melanoma cells. The results indicated that retinoids at concentrations of up to 10(-6) M did not significantly affect type IV collagenolytic activity in these cells in vitro. Since type IV collagenolytic enzyme may be involved in the metastatic potential of tumour cells, it appears that retinoids do not affect the metastatic potential of melanoma cells by affecting type IV collagenolytic activity.

Topics: Cells, Cultured; Etretinate; Humans; Isotretinoin; Melanoma; Microbial Collagenase; Neoplasm Metastasis; Retinoids; Skin Neoplasms; Tretinoin; Vitamin A

Investigation of retinoids for anticancer activity in humans, either in the chemopreventive or treatment mode, has been little studied. We summarize here our ongoing investigations in four different areas: (1) secondary prevention of cervical dysplasia with topical application of all-trans-retinoic acid; (2) adjuvant treatment of resected high-risk stage I and II malignant melanoma with bacille Calmette Guérin (BCG) plus or minus oral vitamin A; (3) topical vitamin A acid therapy for cutaneous metastatic melanoma; an (4) oral isotretinoin as an anticancer agent.

Topics: Diterpenes; Female; Humans; Isomerism; Isotretinoin; Melanoma; Neoplasms; Palmitates; Retinyl Esters; Skin Neoplasms; Tretinoin; Uterine Cervical Dysplasia; Vitamin A