Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A phase I trial was performed to determine the toxicity and efficacy of isolated hepatic perfusion with tumour necrosis factor alpha (TNF) and melphalan (Alkeran) under mild hyperthermic conditions. Eleven patients with unresectable metastatic malignancies in the liver (malignant melanoma, leiomyosarcoma, colorectal cancer) underwent the procedure. Compared to our earlier experience with melphalan and cis-platinum under hyperthermic conditions (41.7 degrees C), this phase I study with TNF 30-200 micrograms and melphalan ).5 mg/kg body weight under 39 degrees C hyperthermia neither improved the response rate nor decreased the serious adverse effects. Two patients died within the first postoperative month owing to coagulopathy or multiple organ failure. Five patients were reoperated owing to postoperative bleeding. Three of six patients with liver metastases from malignant melanoma or leiomyosarcoma and none of five patients with liver metastases from colorectal cancer showed a partial response.
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PMID:Isolated hepatic perfusion with extracorporeal oxygenation using hyperthermia TNF alpha and melphalan: Swedish experience. 967 Feb 74

Tumor necrosis factor (TNF) is a highly cytotoxic cytokine. However, due to its severe side effects, the only clinical situation allowing its administration in humans is isolated limb perfusion (ILP). Early studies have shown that TNF alone is of limited efficacy even at high doses via ILP, and that a chemotherapeutic agent needs to be added. The most commonly used drug in this setting is melphalan which is considered to be synergistic with TNF. However, since melphalan has not been commonly used in sarcoma, we believed that confirmation of its synergistic effect with TNF in an experimental sarcoma model could prove valuable for future drug choice. B16F10 melanoma and CT26 colon carcinoma cells were injected subcutaneously (s.c.) into mice, while GF fibrosarcoma cells were injected s.c. into the hindleg of Wistar rats. The animals were then divided into four treatment groups: TNF alone, melphalan alone, TNF and melphalan, and 0.9% NaCl controls. Mice were treated with intraperitoneal injections and rats by ILP. TNF dosage was 20 microgram for mice and 200 microgram for rats. Melphalan was given at 5-10 mg/kg for both mice and rats. Results showed synergism of TNF and melphalan in both modes of therapy. In the systemic administration groups (mice carrying B16F10 and CT26 tumors), tumors increased in size in all but the combined TNF-melphalan group. In the regional delivery groups (rats carrying GF sarcoma cells treated via ILP), there was a 16% decrease in tumor volume in rats treated with TNF alone, a 29% decrease in rats treated with melphalan, and a 75% decrease in the combined TNF-melphalan group. In conclusion, TNF and melphalan proved to be highly synergistic in both systemic and regional delivery. This fact makes melphalan an adequate choice for TNF perfusion in advanced limb malignancies.
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PMID:Synergism of tumor necrosis factor-alpha and melphalan in systemic and regional administration: animal study. 977 89

CY and L-PAM potentiated specific anti-tumor response in addition to their killing effect. The immunomodulating effect of a low dose of either CY or L-PAM was expressed in mice bearing large s.c. MOPC-315 plasmacytoma tumors. Cured mice were resistant to a challenge dose of the syngeneic tumor and their spleens contained specific cytotoxic T cells. Induction of specific anti-tumor response by a low dose of alkylating drugs was due to expression of "latent anti-tumor" capability. This fitted with the conception that "suppressed concomitant immunity" occurring in tumor-bearing animals can be activated. The immunomodulating activity of alkylating drugs was related to enhancement of T-cell functions:impairment of suppressor T-cell activity,enhancement of effector T-cell activity and increase in production of cytokines at the tumor site. The target tumor killing activity of a low dose alkylating drug was dissociated from its immunomodulating activity by treating mice bearing a tumor resistant to an alkylating drug. A low dose of CY had an immunomodulating effect in human cancer such as reduction of ConA-induced suppressor cell activity in melanoma, some improvement in addition to use of melanoma vaccine, and potentiation of DTH in cancer patients. The immunomodulating effect of alkylating drugs suggest that their use might be beneficial not only for killing tumor cells but also for promoting specific anti-tumor immune response.
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PMID:Immunomodulating anticancer alkylating drugs: targets and mechanisms of activity. 1146 19

Isolated limb infusion (ILI) is an attractive, less complex alternative to isolated limb perfusion (ILP). It has a lower morbidity in treating localized recurrences and in transit metastases of the limb for tumours such as melanoma, Merkel cell tumour and Kaposi's sarcoma, allowing administration of high concentrations of cytotoxic agent to the affected limb under hypoxic conditions. Melphalan is the preferred cytotoxic agent for the treatment of melanoma by ILP or ILI. We report pharmacokinetic data from 12 patients treated by ILI for tumours of the limb in Brisbane. The kinetics of drug distribution in the limb was calculated using a two-compartment vascular model, where both tissue and infusate act as well-stirred compartments. Analysis of melphalan concentrations in the perfusate during ILI showed good agreement between the values measured and the concentrations predicted by the model. Recirculation and wash-out flow rates, tissue concentrations and the permeability surface area product (PS) were calculated. Correlations between the PS value and the drug concentrations in the perfusate and tissue were supported by the results. These data contribute to a better understanding of the distribution of melphalan during ILI in the limb, and offer the opportunity to optimize the drug regimen for patients undergoing ILI.
Melanoma Res 2001 Aug
PMID:Pharmacokinetics and pharmacodynamics of melphalan in isolated limb infusion for recurrent localized limb malignancy. 1147 32

Primary limb melanoma may recur in terms of satellitosis, in transit metastases and/or regional node involvement. Hyperthermic antiblastic perfusion (HAP) permits the isolation of involved extremity from the systemic circulation and to deliver high doses of antineoplastic drugs. The association of cytostatic drugs to hyperthermia (> or = 41.5 degrees C) results in a synergistic effect with an increased therapeutic effectiveness. The overall 5 and 10-year survival rates in relation to the disease stages are st. II 75% and 67%; st. IIIA 59% and 42%; st. IIIAB 36% and 30% respectively. The results confirm that HAP is considered the treatment of choice of loco-regional spreading limb melanoma. Recently, the tumor necrosis factor (TNF) has been combined with Melphalan and hyperthermia. This trimodality association seems to be superior to Melphalan and hyperthermia alone only in patient with bulky tumors (i.e., multiple nodules), as a matter of fact the complete tumor response rates observed in these patients have been 67% and 20% respectively. The greater effectiveness of trimodality association has to be confirmed by multicentric randomized trials.
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PMID:[Anti-blastic hyperthermic perfusion in the treatment of melanoma of the extremities in the loco-regional diffusion phase]. 1290 6

Hypoxic antiblastic stop-flow perfusion (SFP) has recently been proposed as a therapeutic option for patients with locally advanced tumors. We report on the clinical and pharmacological results of our prospective study of limb SFP for the treatment of in transit melanoma metastases. Twenty-three patients with limb-sited melanoma metastases were treated with melphalan (10 mg/l) based pelvic (n=11, group A) or femoral (n=12, group B) SFP under hypoxic conditions. Systemic and locoregional toxicity, tumor response rate, and local progression-free survival were analyzed. Melphalan concentrations were measured in the perfusate and systemic circulation during SFP, and after 30-min hemofiltration. Perfusate-to-plasma leakage was assessed using a scintigraphic method. No postoperative deaths occurred. Mild locoregional toxicity was observed in 5 patients (18%), and systemic toxicity was mild to severe in 8 patients (30%), the incidence being higher in group A. Tumor response rate (complete + partial response) and time to local disease progression were significantly different in group A and B (9% vs 58% and 7 vs 13 months, respectively). The pharmacokinetic study showed that pelvic SFP was associated with a higher leakage rate and a lower area under the curve ratio than femoral SFP (44% vs 31% and 5.6 vs 9.8, respectively). Limb SFP is a feasible and relatively simple procedure. Toxicity and tumor response rates strictly depend upon drug leakage control. Further efforts should be made to exploit the potential anti-tumor activity of this novel locoregional drug delivery system.
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PMID:Hypoxic antiblastic stop-flow limb perfusion: clinical outcome and pharmacokinetic findings of a novel treatment for in transit melanoma metastases. 1537 19

Hyperthermic antiblastic perfusion (HAP) has been proven to be an effective treatment of loco-regional spreading limb melanoma. The mean complete response (CR) rate obtained is 54%, with an objective responses (OR) rate ranging between 70% and 100%. Recently, Tumor Necrosis Factor (TNFalpha) has been employed at high dosages (3-4 mg) in association to Melphalan and hyperthermia. This trimodality combination increased the percentage of CR (70%-90%), but systemic toxicity was also reported due to high TNF doses. A phase I - II study was undertaken in order to assess the MTD of TNFalpha in association to true hyperthermia (41.5 degrees C) and Melphalan. Twenty patients affected with stages IIIA (9 patients), IIIAB (10 patients), and IV (1 patient) were enrolled in this study. The trimodality treatment did not increase the local and systemic toxicity. CR was observed in 70% of the patients, PR in 20% with on OR rate of 90%. These figures are overlapping those obtained with high TNF dosages. No correlation was observed between tumor responses and TNF doses. Taking into account that 70% of our patients have been treated with TNF dosages between 0.5 mg on 1.6 mg, we conclude that 1 mg is the best dosage to be applied during HAP. Patients with bulky tumor are the best candidate to TNF perfusion, because no differences have been observed in terms of CR in patients with low tumor burden treated with TNF-Melphalan-hyperthermia or Melphalan-hyperthermia.
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PMID:Hyperthermic antiblastic perfusion with TNFalpha and melphalan in stage III limb melanoma patients: A phase I - II SITILO study. 1676 14

Isolated limb perfusion (ILP) is currently considered the standard treatment for melanoma patients with extensive in-transit disease, and L-PAM, combined or not with TNF, represents the most active drug. We here report on our clinical experience with TNF-based limb perfusion. Thirty-seven stage III patients underwent TNF-based limb perfusion, 22 with bulky disease, 15 with recurrences after perfusion with L-PAM. Ten patients were enrolled in a phase I-II study and treated with escalating doses of TNF (0.5-3 mg). The impact of disease burden, temperature, perfusion duration was assessed on tumor response. No postoperative death was observed. No significant systemic toxicity was recorded. Locoregional toxicity was G5 in one patient, G3 in 2, G2 in 9 and G1 in 25. Twenty-four (66%) patients had complete response, 11 (31%) partial and 1 (3%) no change. After a median follow-up of 20 months 14 (38%) patients are NED, 10 (27%) are AWD and 13 (35%) DOD. No significant statistical difference for tumor response were seen for disease burden, ILP temperatures and duration. Our results showed that it is possible to modify the perfusion schedule, without compromising the response rate but with lower cost and toxicity.
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PMID:TNF-based limb perfusion for cutaneous melanoma in transit metastases: suggestions for modification of the perfusional schedule. 1676 15

We described a 57-yr-old male diagnosed with cutaneous T-cell lymphoma that had failed multiple treatment options, as his disease was mainly confined to one limb. We attempted a novel approach in this condition using a technique of intra-arterial limb infusion with cytotoxic agent Melphalan (ILI) which has been proven beneficial in management of localised malignant melanoma. This treatment approach was well tolerated with mild myelosuppression and moderate limb toxicity. However, a significant improvement has been noted in the affected limb. This case demonstrated the successful use of isolated limb infusion with Melphalan in the management of localised cutaneous T-cell lymphoma. However, this result needs to be confirmed and further study is recommended. We are unaware there have been similar cases reported in the literature.
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PMID:Isolated limb infusion with cytotoxic agent for treatment of localized refractory cutaneous T-cell lymphoma. 1689 71

Two forms of regional chemotherapy for the treatment of advanced melanoma or sarcoma of the extremity are isolated limb perfusion (ILP) and the more recently described isolated limb infusion (ILI). Melphalan is the most commonly employed agent in both ILP and ILI, although it is often used in conjunction with other cytotoxic and/or biologic therapies. While ILP and ILI are far more effective for the treatment of extremity disease than is systemic therapy, there is still significant room for improvement in outcomes, from the standpoint of both response rate and toxicity. An understanding of the pharmacokinetics of regional chemotherapy would allow for the prediction of tumor response and toxicity and therefore patient outcomes. In addition, elucidating the mechanisms of drug resistance would lead to opportunities to develop effective chemo-modulators that enhance the effectiveness of ILP and ILI. This paper reviews progress in these two key areas of active investigation.
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PMID:Pharmacokinetics & drug resistance of melphalan in regional chemotherapy: ILP versus ILI. 1839 2


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