melphalan and Hypoxia

For patients with melanoma metastases in the pelvic and groin regions, the median survival time (MST) was 8 mo with old treatments, whereas today is approximately 20 mo with new target therapy and novel immunotherapy. Unfortunately, approximately 30% of patients are nonresponsive to these new drugs.. Thirty-six patients, previously progressing after standard treatments, collectively received 146 melphalan (30 mg/m. The median follow-up time was 15 mo. Among 36 patients, three patients were alive without evidence of disease after 62, 95, and 118 mo, respectively. Thirty-three patients died of melanoma. The overall MST was 15 mo. The 5-y survival rate was 8%. The MST was 37 mo for stage IIIB; 19 mo for stage IIIC; and 6 mo for stage IV. The MST was 11 mo for patients with ≥1 mitosis per mm. Pelvic/inguinal perfusion is a safe and feasible treatment for patients with advanced melanoma. Further studies are necessary to establish if it may play a role in patients who fail current systemic therapies.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Combined Modality Therapy; Female; Follow-Up Studies; Hemofiltration; Humans; Hypoxia; Male; Melanoma; Melphalan; Middle Aged; Pelvic Neoplasms; Prospective Studies; Skin Neoplasms; Survival Analysis; Treatment Outcome

Developments in balloon catheter methodology have made hypoxic abdominal perfusion (HAP) with anti-tumour agents possible with only minimal invasive surgery. The initial reports on this modality and celiac axis stop-flow infusion for treatment of pancreatic cancer were very promising in terms of tumour response, median survival and pain reduction. Recent reports, however, have not been able to confirm these results and some have disputed the efficacy of these currently still applied treatment modalities.. Twenty-one patients with advanced pancreatic carcinoma were included in a phase I-II trial of HAP with MMC and Melphalan followed by celiac axis infusion (CAI) with the same agents six weeks later. Tumour response was assessed by abdominal-CT and by determining tumour markers. Effect on pain reduction was assessed by evaluation of pain registration forms.. HAP resulted in augmented regional drug concentrations. One patient died after CAI due to acute mesenterial ischaemia. One agent-toxicity related death was observed in the phase-I study. Significant hematological toxicity was observed after HAP and CAI at MTD. No patients were considered resectable after treatment. Median survival after HAP was 6 months (range 1-29). Pain reduction was experienced by only 5/18 patients and was short-lived.. In contrast to earlier reports HAP and CAI with MMC and Melphalan did not demonstrate any benefit in terms of tumour response, median survival and pain reduction, compared to less invasive treatment options. As this treatment was associated with significant toxic side-effects and even one procedure related death, we do not consider this a therapeutic option in patients with advanced pancreatic cancer.

Topics: Aged; Antineoplastic Agents; Balloon Occlusion; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Hypoxia; Infusions, Intra-Arterial; Male; Melphalan; Middle Aged; Mitomycin; Pain; Pain Measurement; Pancreatic Neoplasms; Remission Induction; Treatment Outcome

Hypoxic pelvic and limb perfusion by means of a balloon occlusion technique was evaluated in patients with recurrent melanoma of the lower limbs who were non-responders to isolated hyperthermic limb perfusion or who were not eligible for this procedure. A pilot study was performed in 17 patients, who underwent hypoxic pelvic and limb perfusion with 50 mg/m(2) of melphalan or 50 mg/m(2) of melphalan and 25 mg/m(2) of mitomycin C. Each procedure was followed by haemofiltration. A leakage monitoring study was performed in five of the 17 patients. The response rate and time to disease progression were the primary endpoints, with overall survival as the secondary endpoint. During the procedures there were no technical, haemodynamic or vascular complications, and no deaths occurred during surgery or in the postoperative period. Significant leakage (median 40%) was measured in the five patients studied. No severe systemic or regional toxicity was observed. After one course of treatment, the objective response rate was 47% (95% confidence interval 22.5-71.5%), the median time to disease progression was 10 months (range 2-40 months), and the 3 year overall survival was 20%. Hypoxic pelvic and limb perfusion seems to be a safe and effective treatment for patients with unresectable recurrent limb melanoma who are not eligible for isolated hyperthermic limb perfusion. Due to the non-homogeneity of the study, with some patients receiving a combination of melphalan and mitomycin C and others receiving only melphalan, it is not possible to make definite conclusions with regard to efficacy. Further studies are necessary to establish whether the response rates can be improved by using different drug regimens.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Disease Progression; Extremities; Female; Humans; Hypoxia; Male; Maximum Tolerated Dose; Melanoma; Melphalan; Middle Aged; Mitomycin; Neoplasm Recurrence, Local; Pilot Projects; Skin Neoplasms; Survival Rate; Time Factors

The treatment of patients with advanced or recurrent pelvic melanoma, which are often associated with lesions in the lower limbs, is still unsatisfactory and controversial. A simplified hypoxic pelvic and limb perfusion has been recently recommended to provide therapeutic options for palliation and possibly cure.. A nonrandomized and noncontrolled phase II experimental study was performed in 11 patients with symptomatic unresectable recurrent melanoma of the pelvis and limb. Patients were submitted to hypoxic pelvic and limb perfusion with 25 mg/m(2) of melphalan, 50 mg/m(2) of cisplatin, 300 mg/m(2) of dacarbazine, and 75 mg/m(2) of epirubicin by means of a simplified balloon occlusion technique. Response rate and time to disease progression were the primary endpoints; overall survival was the secondary endpoint.. During the procedures there were no technical, hemodynamic, or vascular complications, and no deaths occurred during surgery or in the postoperative period. Response rate was 82% (95% confidence interval, 58% to 100%). Median time to disease progression was 12 months (range 9 to 30 months). Three-year overall survival was 34%.. Hypoxic pelvic and limb perfusion is a safe and good palliative treatment for patients with unresectable recurrent melanoma. Further studies are necessary to to confirm these data and to establish if refinements can be made with acceptable toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Dacarbazine; Disease Progression; Disease-Free Survival; Epirubicin; Female; Hemodynamics; Humans; Hypoxia; Leg; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Recurrence, Local; Palliative Care; Pelvis; Skin Neoplasms; Treatment Outcome

There is increasing evidence that tumor hypoxia plays a significant role in the chemoresistance of melanoma, but to our knowledge, real-time tumor oxygenation during isolated limb infusion (ILI) has not been studied. We sought to demonstrate the feasibility of measuring real-time alterations in tissue oxygenation.. Consecutive patients with histologically confirmed in-transit melanoma were enrolled onto a prospective single-arm pilot study and administered the hypoxia marker drug EF5. All patients were treated with ILI. Optical spectroscopy readings were obtained at three locations: two discrete target lesions and one normal skin control. Measurements were taken at 11 predefined time points during ILI.. A total of six patients were enrolled onto this pilot study. Intratumor and normal skin optical spectroscopy readings were found to have discrete inflection points throughout the duration of therapy, corresponding with established time points. Baseline hypoxia as measured by both optical spectroscopy and EF5 immunofluorescence was variable, but on the basis of optical spectra, tumors appeared to become more hypoxic compared to normal skin after tourniquet application. The optical hypoxia signature was variable between patients while hemoglobin absorption increased.. To our knowledge, this is the first use of real-time optical spectroscopy to evaluate oxygenation and perfusion within melanoma lesions during regional chemotherapy. We report our development of this new noninvasive means of assessing tumor vascular function, which has the potential to be a powerful tool for noninvasive examination of the melanoma tumor microenvironment.

Topics: Aged; Antineoplastic Agents, Alkylating; Etanidazole; Feasibility Studies; Female; Follow-Up Studies; Humans; Hydrocarbons, Fluorinated; Hypoxia; Indicators and Reagents; Male; Melanoma; Melphalan; Middle Aged; Neoplasm Staging; Pilot Projects; Prognosis; Prospective Studies

To investigate potential synergistic interactions between bioreductive agents, either NLCQ-1 or tirapazamine (TPZ) and two alkylating chemotherapeutic drugs, and how such interactions compare in vitro and in vivo.. V79 cells (in vitro studies) and the SCCVII/C3H murine tumor model (in vivo studies) were used. The alkylating chemotherapeutic agents examined were cisplatin (cisDDP) and melphalan (L-PAM). In vivo, all agents were administered by i.p. injection wherein NLCQ-1 and TPZ were given at equitoxic doses of 10 and 23 mg/kg, respectively. Optimal administration schedules and dose modification factors (DMF) were determined in vivo for the antitumor effect or bone marrow toxicity by using the in vivo-in vitro clonogenic assay as the endpoint.. A schedule-dependent synergistic interaction was observed between NLCQ-1/TPZ and each alkylating agent, both in vitro and in vivo, and an optimal potentiation was obtained when each bioreductive agent was administered prior to each chemotherapeutic drug. However, significant DMF values and an in vivo therapeutic index (TI) was obtained only with NLCQ-1. Limited mechanistic studies in V79 cells by using the alkaline comet assay demonstrated that hypoxic preincubation with NLCQ-1 increases the cross-links induced by subsequent aerobic exposure to cisDDP.. These results verify our previous observations in EMT6 tumors and suggest a potential clinical use of NLCQ-1 as a synergistic adjuvant to chemotherapy with alkylating agents against solid tumors possessing hypoxic regions.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Cisplatin; Comet Assay; Cricetinae; Drug Synergism; Female; Hypoxia; Imidazoles; In Vitro Techniques; Melphalan; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Quinolines; Tirapazamine; Triazines

Addition of tumour necrosis factor-alpha (TNF) to hypoxic abdominal perfusion (HAP) and hypoxic pelvic perfusion (HPP) with chemotherapeutic agents for treatment of un-resectable malignancies may lead to similar enhanced anti-tumour effects as are observed when TNF is added to isolated limb perfusions (ILP) with Melphalan. Here, we validate the methodology of HAP and HPP using balloon catheter techniques, and investigate the distribution of TNF, Melphalan and Mitomycin C (MMC) over the regional and systemic blood compartments when applying these techniques.. Twelve pigs underwent HAP or HPP with TNF, Melphalan and MMC for 20 min. Throughout and after the procedures blood samples were obtained from hepatic, portal and systemic blood compartments and plasma concentrations of perfused agents were determined.. We demonstrated that HAP and HPP result in temporary loco-regional concentration advantages of all perfused agents, although from start of perfusion significant systemic leakage occurred.. On basis of these results it seems that the advantage in terms of regional plasma concentration of TNF may be insufficient for TNF-mediated effects to occur, making future addition of this cytokine to these procedures in the clinical setting questionable. The observed regional concentration advantages of MMC and Melphalan, however, warrant further studies on clinical application of these agents in both settings.

Topics: Abdominal Neoplasms; Animals; Antineoplastic Agents; Balloon Occlusion; Chemotherapy, Cancer, Regional Perfusion; Hypoxia; Melphalan; Mitomycin; Models, Animal; Pelvic Neoplasms; Swine; Tumor Necrosis Factor-alpha

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.

Topics: Aged; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Disease-Free Survival; Extremities; Female; Humans; Hypoxia; Male; Melanoma; Melphalan; Middle Aged; Prospective Studies; Skin Neoplasms; Treatment Outcome

In the treatment of cancer, isolated limb perfusion (ILP) allows what would be a lethal systemic dose of cytotoxic drugs to be administered directly to a tumour site of an extremity. Unfortunately, ILP is a complex, expensive, time-consuming treatment that requires general anaesthesia, vascular surgery and expertise with extracorporeal circuits that may not be available outside a cardiac centre. By streamlining the traditional ILP protocols and eliminating the oxygenator from the circuit, an equally safe and effective technique of hypoxic hyperthermic isolated limb perfusion has been developed.

Topics: Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Clinical Protocols; Extracorporeal Circulation; Extremities; Humans; Hyperthermia, Induced; Hypoxia; Melanoma; Melphalan; Oxygenators, Membrane

Treatment with the DNA topoisomerase inhibitors etoposide, doxorubicin, and camptothecin, and with the alkylating agents cisplatin and melphalan, caused peroxide accumulation and apoptosis in U-937 human promonocytic cells. Preincubation with the reduced glutathione (GSH) synthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO) always potentiated peroxide accumulation. However, although GSH depletion potentiated the toxicity of cisplatin and melphalan, occasionally switching the mode of death from apoptosis to necrosis, it did not affect the toxicity of the other antitumor drugs. Hypoxia or preincubation with antioxidant agents attenuated death induction, apoptotic and necrotic, by alkylating drugs. The generation of necrosis by cisplatin could not be mimicked by addition of exogenous H(2)O(2) instead of BSO and was not adequately explained by caspase inactivation nor by a selective fall in ATP content. Treatment with cisplatin and melphalan caused a late decrease in mitochondrial transmembrane potential (DeltaPsim), which was much greater during necrosis than during apoptosis. The administration of the antioxidant agents N-acetyl-l-cysteine and butylated hydroxyanisole after pulse treatment with cisplatin or melphalan did not affect apoptosis but attenuated necrosis. Under these conditions, both antioxidants attenuated the necrosis-associated DeltaPsim decrease. These results indicate that oxidation-mediated alterations in mitochondrial function regulate the selection between apoptosis and necrosis in alkylating drug-treated human promonocytic cells.

Topics: Adenosine Triphosphate; Alkylating Agents; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; Buthionine Sulfoximine; Camptothecin; Cell Death; Cisplatin; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Doxorubicin; Enzyme Inhibitors; Etoposide; Flow Cytometry; Glutathione; Humans; Hydrogen Peroxide; Hypoxia; Immunoblotting; Melphalan; Membrane Potentials; Mitochondria; Monocytes; Necrosis; Nucleic Acid Synthesis Inhibitors; Oxygen; Radiation-Protective Agents; Reactive Oxygen Species; Spectrometry, Fluorescence; Time Factors; Topoisomerase I Inhibitors; U937 Cells

An isolated limb perfusion (ILP) model using soft tissue sarcoma-bearing rats was used to study prerequisites for an effective ILP, such as oxygenation of the perfusate, temperature of the limb, duration of the perfusion and concentration of tumour necrosis factor (TNF). Combination of 50 microg TNF and 40 microg melphalan demonstrated synergistic activity leading to a partial and complete response rate of 71%. In comparison to oxygenated ILP, hypoxia was shown to enhance anti-tumour activity of melphalan alone and TNF alone but not of their combined use. Shorter perfusion times decreased anti-tumour responses. At a temperature of 24-26 degrees C, anti-tumour effects were lost, whereas temperatures of 38-39 degrees C or 42-43 degrees C resulted in higher response rates. However, at 42-43 degrees C, local toxicity impaired limb function dramatically. Synergy between TNF and melphalan was lost at a dose of TNF below 10 microg in 5 ml perfusate. We conclude that the combination of TNF and melphalan has strong synergistic anti-tumour effects in our model, just as in the clinical setting. Hypoxia enhanced activity of melphalan and TNF alone but not the efficacy of their combined use. For an optimal ILP, minimal perfusion time of 30 min and minimal temperature of 38 degrees C was mandatory. Moreover, the dose of TNF could be lowered to 10 microg per 5 ml perfusate, which might allow the use of TNF in less leakage-free or less inert perfusion settings.

Topics: Animals; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Drug Synergism; Hindlimb; Hypoxia; Male; Melphalan; Rats; Rats, Inbred BN; Temperature; Tumor Necrosis Factor-alpha

Topics: Abdominal Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Doxorubicin; Female; Fluorouracil; Humans; Hypoxia; Melphalan; Mitomycin

The enhancement of melphalan toxicity was observed by preincubation of V-79- 379A cells in spinner culture with multiple doses of misonidazole (miso) or SR-2508 under hypoxic conditions. Chemosensitization was shown to be a function of sensitizer concentration and duration of exposure to the alkylating agent. A preincubation exposure of cells with 5 mM miso reduced endogenous cell thiols to less than 5% of controls and enhanced melphalan toxicity by a factor of 4.7. Cells preincubated with miso not only had lower levels of nonprotein thiols, but also were shown to have altered levels of intracellular calcium and a lower threshold to oxidative stress as measured by toxicity to cysteamine or H2O2. Preincubated cells, hypoxic cells, and cells receiving moderate hyperthermia (42.5 degrees C for 3 hr) all showed increased sensitivity to either cysteamine or H2O2. The increased killing of preincubated cells by cysteamine was shown to be similar to that of H2O2, and the dramatic reduction of cysteamine toxicity by catalase indicated H2O2 was the major reaction associated with this effect. These results indicate that preincubated cells exhibit a variety of biological effects that may significantly influence their response to further treatment with drugs or radiation, especially where peroxidative and free radical mechanisms are involved. The depletion of endogenous thiols, calcium disturbance, and vulnerability to oxidative stress are factors to be considered when interpreting mechanisms of combined drug action and effects that may potentially be exploited in terms of therapeutic gains.

Topics: Animals; Cell Survival; Cells, Cultured; Cricetinae; Cysteamine; Dose-Response Relationship, Drug; Drug Resistance; Etanidazole; Hydrogen Peroxide; Hyperthermia, Induced; Hypoxia; Melphalan; Nitroimidazoles; Radiation Tolerance; Radiation-Sensitizing Agents; Time Factors

Survival of hypoxic cells exposed to misonidazole at 37 degrees C show an initial lag period after which survival decreases exponentially with time. Hypoxic cells incubated with misonidazole for a time equivalent to that of the lag period on the survival curve show increased sensitivity when subsequently given x-irradiation. This is consistent with previously published observations. In addition, preincubation of hypoxic cells with misonidazole ata 37 degrees C also renders cells more sensitive to subsequent treatments by heat or melphalan, mustine and cis-Pt(II). Preincubation must be in hypoxia for cells to become sensitive to a second insult; preincubation in air does not change cellular sensitivity even when this preexposure is 5 mM misonidazole for 3 days. The potential of exploiting a physiological property of most solid tumors, viz., hypoxia, in order to increase sensitivity of tumor cells to cytotoxic agents is discussed.

Topics: Animals; Antineoplastic Agents; Cell Survival; Cells, Cultured; Cisplatin; Cricetinae; Hot Temperature; Hypoxia; Mechlorethamine; Melphalan; Misonidazole; Nitroimidazoles; Radiation-Sensitizing Agents

Topics: Adolescent; Adult; Amputation, Surgical; Bone Neoplasms; Child; Chondrosarcoma; Female; Humans; Hypothermia, Induced; Hypoxia; Lymphoma, Large B-Cell, Diffuse; Male; Melphalan; Methods; Osteosarcoma; Radiation Injuries; Tourniquets