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Danielle Lienard - One of the best experts on this subject based on the ideXlab platform.
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Systemic and Hemodynamic Effects of Recombinant Tumor Necrosis Factor Alpha in Isolation Perfusion of the Limbs
Chest, 1995Co-Authors: Philippe Eggimann, Danielle Lienard, Jean Gerain, René Chioléro, Pierre-guy Chassot, Ferdy LejeuneAbstract:Objective To describe the systemic effects of high-dose recombinant tumor necrosis factor alpha (rTNF-α), recombinant interferon gamma (rIFN-γ), and melphalan administered through hyperthermic Isolation Perfusion of the limbs (IPL) in patients with melanoma and malignant soft-tissue tumors. Design The clinical, hemodynamic, and biologic parameters were recorded after IPL during the postoperative period. Setting Surgical intensive care service of a 1,000-bed tertiary university medical center. Patients Nineteen patients referred to a pluridisciplinary Center for Oncology after relapse of regionally advanced melanoma or soft-tissues tumors, included in a phase 2 therapeutic study. Results Major systemic and hemodynamic changes were observed after IPL in all patients. Ninety-four percent (17/18) of the evaluable patients presented a shock unresponsive to fluid challenge, requiring the continuous Perfusion of vasopressors, inotropic agents, or both. Analysis of hemodynamic data showed two distinctive patterns: a pure distributive shock in nine patients requiring norepinephrine, and a mixed distributive and cardiogenic shock in eight patients requiring vasopressor and inotropic agents. The oxygen parameters were characterized by an increase in both the delivery and the uptake of oxygen, with a prolonged reduced oxygen extraction ratio for most patients. The other observed effects were as follows: transient bilateral or mixed pulmonary infiltrates in all patients; some hematologic disturbances in 83% of patients; infection requiring a modification of the antibiotic prophylaxis in 61% of patients; and some liver toxic reactions in 50% of patients. Very high systemic TNF-α serum bioactivity was found in 12 patients for whom serum samples were available, indicating an early and important rTNF-α leakage from the IPL. No correlations could be found between the levels of TNF-α and the observed systemic effects. Despite the severity of the hemodynamic disturbance, no patient died. Conclusion Major systemic effects, consisting mainly in cardiovascular, respiratory, and hematologic disturbances, were observed in patients after IPL with high-dose of rTNF-α. The likely explanation for these observations is an early rTNF-α leakage related to inadequate IPL technique. These data show that the iatrogenic administration of high circulating TNF levels lead to a “septic shock-like” syndrome without resulting in lethal organ dysfunction.
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Administration of high-dose tumor necrosis factor alpha by Isolation Perfusion of the limbs. Rationale and results.
The Journal of infusional chemotherapy, 1995Co-Authors: Ferdy Lejeune, Danielle Lienard, Bbr Kroon, A. M. M. Eggermont, Schraffordt Koops H, Rosenkaimer F, J. Gérain, Klaase J, J. Vanderveken, P SchmitzAbstract:Recombinant tumor necrosis factor alpha (rTNF alpha) has potent antitumor activity in experimental studies on human tumor xenografts. However, in humans, the administration of rTNF alpha is hampered by severe systemic side effects. The maximum tolerated dose ranges from 350 to 500 mg/m2, which is at least 10-fold less than the effective dose in animals. Isolated Perfusion of the limbs (ILP) allows the delivery of high-dose rTNF alpha in a closed system with acceptable side effects. A protocol with a triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In patients with melanoma-in-transit metastases (stage IIIA or AB), we obtained a 91% complete response rate compared with 52% after ILP with melphalan alone. In unresectable soft tissue sarcomas, this protocol was found to produce a 50% complete response with 87.5% limb salvage, since most tumors became removable. Release of nanograms levels of TNF alpha in the systemic circulation was evident, but control of this leakage and appropriate intensive care resulted in acceptable toxicity. Angiographic, immunohistological, and immunological studies suggest that the efficacy of this protocol is due to a dual targeting: rTNF alpha activates and electively lyses the tumor endothelial cells, while melphalan is mainly cytotoxic to the tumor cells. ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in man.
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Isolated Perfusion of the limb with high-dose tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and melphalan for melanoma stage III. Results of a multi-centre pilot study.
Melanoma research, 1994Co-Authors: Danielle Lienard, Bbr Kroon, A. M. M. Eggermont, Schraffordt Koops H, Rosenkaimer F, Philippe Autier, Ferdy J. LejeuneAbstract:We report an update of a multi-centre pilot study previously published. Fifty-three patients (42 women, 11 men) were accrued between October 1988 and May 1992: 34 had stage IIIA, 15 had stage IIIAB, and four had stage IV melanoma. Most of them had more than five in-transit metastases; 50% had been previously treated by regional chemotherapy. Protocol included 90-min Isolation Perfusion at 40 degrees C with 2-4 mg rTNF-alpha, 0.2 mg rIFN-gamma and 10/13 mg/l melphalan. We prevented severe TNF systemic side effects by administration of dopamine and fluid loading. There has been no toxic death and the toxicity remained acceptable, with only one multi-organ failure (MOF) and no prolonged shock. Response rates remained very high, with 90% complete remission, 10% partial response and no failure. With a median follow-up time of 26 months, there were 12 regional recurrences, 15 distant metastases and nine local and distant recurrences. The median overall survival has been 28 months. We conclude that high-dose rTNF-alpha associated with melphalan in Isolation Perfusion is the therapy of choice for in-transit melanoma metastases.
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In transit metastases of malignant melanoma treated by high dose rTNFα in combination with interferon-γ and melphalan in Isolation Perfusion
World Journal of Surgery, 1992Co-Authors: Danielle Lienard, Ferdy J. Lejeune, Patricia EwalenkoAbstract:To increase the therapeutic efficacy of recombinant tumor necrosis factor alpha (rTNFα) and reduce the systemic side effects, a protocol was designed using Isolation Perfusion of the limbs with hyperthermia for in transit metastases of melanoma. A triple combination of high dose rTNFα + recombinant interferon-gamma (rIFN-γ) + melphalan was chosen because of a synergistic anti-tumor effect of rTNFα with rIFN-γ and of rTNFα with alkylating agents reported in the literature. Twenty-nine patients of mean age 60 years (range 22–82 years) entered the study after informed consent and received a total of 31 Isolation Perfusions with the triple combination. There were 24 women and 5 men with multiple progressive in transit melanoma metastases of the lower limb (stage IIIa or IIIab). rTNFα at the unique dose of 4 mg was injected as a bolus in the arterial line, under mild hyperthermic conditions (40 to 40.5°C) for 90 minutes. rIFN-γ was given subcutaneously on days −2 and −1 and in the perfusate, with rTNFα, at the dose of 0.2 mg. Melphalan was administered in the perfusate at dose giving a concentration of 40 µg/ml. In all the 31 Isolation Perfusions performed in the triple combination protocol, in order to prevent a septic shock-like syndrome which had been encountered in 2 patients treated outside this protocol for sarcoma and carcinoma, the patients received dopamine continuous infusion at 3 µg/kg/min from the start of Isolation Perfusion and for 48 hours, and only showed mild hyptension and very transient chills and temperature. Regional toxicity attributable to rTNFα was minimal. There have been 16 patients with hematologic toxicity consisting of neutropenia (11 cases, 1 case grade 4 and 1 case grade 3) and neutropenia with thrombocytopenia (12 cases, 1 case grade 4 and 4 cases grade 2). Eighteen of 29 patients had been previously treated with melphalan in Isolation Perfusion (n=13) or with cisplatinum (n=2), rTNFα-Melphalan (n=1), or rTNFα alone (n=2). Median follow-up has been 41 weeks. The 29 patients are evaluable: there have been 26 (90%) complete remissions (CR), 3 (10%) partial remissions (PR), and no failures. Actuarial disease-free survival and total survival have been 63% and 73%, respectively, at 12 months. In all cases, softening of the nodules was obvious within 3 days after Isolation Perfusion and time to definite response ranged between day 6 and 22. This interim analysis of a phase II study suggests that high dose of rTNFα can be administered with acceptable toxicity by Isolation Perfusion with dopamine and hyperhydration. Tumor responses can be evidenced in all patients, with 90% CR. Furthermore, combination of rTNFα, rIFN-γ, and melphalan seems to achieve high efficacy with minimal toxicity, even after failure of prior therapy with melphalan alone. Se diseñó un protocolo que utiliza la perfusión aislada de las extremidades con hipertermia a fin de incrementar la eficacia terapéutica del factor necrotizante tumoral alfa recombinante (rFNTα) y reducir sus efectos secundarios sistémicos, en el tratamiento de metástasis en tránsito del melanoma. Se escogió una combinación triple de alta dosis de rFNTα + interferóngamma recombinante (rIFN-γ) + melfalán en virtud del efecto sinergístico antitumoral del rTNFα con el IFN-γ y del rTNFα con los agentes alquilantes informados en la literatura. Veintinueve pacientes con edad promedio de 60 años (rango 22–82) ingresaron al estudio bajo consentimiento informado y recibieron un total de 31 Perfusiones aisladas con la triple combinación. Hubo 24 mujeres y 5 hombres con metástasis en tránsito de melanoma de la extremidad inferior (estado IIa o IIIab). El rTNFα en la dosis única de 4 mg fue inyectado en bolo en la línea arterial, bajo condiciones levemente hipertermicas (40 a 50°C) por 90 minutos. El rIFN-γ fue administrado en los días −2 y −1 en el líquido perfusión, con rTNFα en la dosis de 0.2 mg. El melfalán fue administrado en el líquido de perfusión en una dosis para proveer una concentración de 40 µg/ml. En todos los casos de perfusión aislada en el protocolo de triple combinación, y con el objeto de prevenir un cuadro del tripo de “shock-syndrome” que había sido observado en 2 pacientes tratados por sarcoma y carcinoma por fuera de este protocolo, se administró dopamina en infusión continua a una rata de 3 µg/kg/min desde el comienzo de la pefusión aislada y, por 48 horas; los pacientes sólo exhibieron hipotensión leve y escalofríos y fiebre transitorios. La toxicidad regional atribuible as rTNFα fue mínima. Se han presentado 16 casos con toxicidad hematológica consistente en nuetropenia (11 casos, uno grado 4 y uno grado 3) y neutropenia con trombocitopenia (12 casos, uno grado 4 y cuatro grado 2). Dieciocho de 29 pacientes habían sido previamente tratados con melfalán en perfusión aislada (13/29) o con cisplatino (2/29), rTNFα-melfalán (1/29) or rTNFα solamente (2/29). El promedio del sequimiento fue 41 semanas. Los 29 pacientes son valorables: ha habido 26 remisiones completas (90%), 3 remisiones parciales (10%) y ninguna falla. Las tasas de sobrevida actuarial libre de enfermedad y de sobrevida total han sido 63% y 73%, respectivamente, a 12 meses. En la totalidad de los casos apareció evidente el ablandamiento de los nódulos en los primeros 21 días después de la perfusión aislada y el intervalo hasta la respuesta difinitiva varió entre el día 6 y el día 22. El análisis interim de un estudio de fase II sugiere que la alta dosis de rTNFα puede ser administrada con aceptable toxicidad por perfusión aislada con dopamina e hiperhidratación. Las respuestas tumorales pueden ser evidenciadas en la totalidad de los pacientes, con 90% de remisión completa. Además, la combinación de rTNFα, rIFN-γ y melfalán parece ser de elevada eficacia con toxicidad mínima, aún después de una falla terapéutica con melfalán sólo. Pour augmenter l'efficacité thérapeutique du facteur recombinant de nécrose tumorale alpha (rTNFα) et pour réduire les effets secondaires, on a élaboré un protocole utilisant une Perfusion isolée des extrémités associée à une hyperthermie chez les patients atteints de métastases d'un mélanome. En raison d'un effet synergique antitumoral, de rTNFα et de l'interféron gamma recombinant (rIFN) d'une part et de rTNFα et des agents alkylisants d'autres part (effet rapporté dans la littérature), on a utilisé une triple combinaison de rTNFα à hautes doses, rIFN et melphalan. Vingt neuf patients d'âge moyen de 60 ans (extrêmes 22–82 ans) ont été inclus dans cette étude après avoir donné leur consentement éclairé. Ils ont reçu un total de 31 Perfusions de la tripe association. Il y avait 24 femmes et 5 hommes ayant des métastases multiples extensives des membres inférieurs (stade III a ou II ab). rTNFα a été administré à une dose unique de 4 mg injectée en bolus par voie artérielle, dans des conditions d'hyperthermie modérée (40 à 40.5°C) pendant 90 minutes. rTNFα a été donné en souscutanée aux jours −2 et −1 mélangé à la Perfusion de rTNFα à la dose de 0.2 mg. Le melphalan a été administré à la concentration de 40 mg/ml. Pour éviter un syndrome de choc rencontré chez deux patients traités hors protocole pour sarcome et carcinome, tous les patients de ce protocole ont reçu de la dopamine en Perfusion continue à la dose de 3 µg/kg/mn depuis le début de la Perfusion et pendant 48 heures, et n'ont eu qu'une hypotension modérée avec des frissons transitoires. La toxicité attribuée au rTNFα était minime. On a eu 16 cas de toxicité hématologique comprenant une neutropénie (11 cas, 1 grade 4, 1 grade 3) et neutropénie avec thrombopénie (12 cas, 1 grade 4, 4 grade 2). Dix huit patients avaient déjà été traités par Melphalane en Perfusion isolée (13/39) ou en association avec du cisplatinium (2/29) ou par l'association rTNFα-melphalan (1/29) ou le rTNFα seul (2/29). Le suivi moyen était de 41 semaines. Sur les 29 patients évalués, il y a eu 26 rémissions complètes (RC) (90%), 3 rémissions partielles (RP) (10%) et ancun décès. Les survies actuarielles sans maladie et globale à 12 mois sont respectivement de 63 et de 73%. Dans tous les cas, les nodules se sont assouplis en moins de 3 jours après le début de la Perfusion. Le délai de réponse au traitement variait entre 6 et 22 jours. L'analyse intermédiaire de l'étude de phase II suggère que de fortes doses de rTNFα peuvent être administrées avec une faible toxicité en Perfusion associées à la dopamine et à une hyperhydratation. La réponse tumorale était évidente chez tous les patients avec une CR de 90%. De plus, l'association de rTNFα, IFN et melphalan semble donner une grande efficacité avec une toxicité minime, même en cas d'échec antérieur avec le melphalan utilisé seul.
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High serum levels of TNF-α after its administration for Isolation Perfusion of the limb
Cytokine, 1992Co-Authors: Jean Gerain, Danielle Lienard, Patricia Ewalenko, Ferdy J. LejeuneAbstract:Abstract In a phase II study, 18 patients with locally spreading melanoma or sarcoma of lower limb were treated by Isolation Perfusion (ILP) with hyperthermia and local infusion of high dose of recombinant human tumor necrosis factor α (rHuTNF-α) (4 mg). Bioactive TNF-α and interleukin 6 (IL-6) serum levels were measured serially, In the limb, TNF-α rapidly reached a plateau at 2 μ/ml, while IL-6 appeared later and progressively increased until the end of ILP. In the systemic circulation TNF-α rose up to a median concentration of 31 ng/ml after 1 hour, then decreased and became negligible after 6 hours. IL-6 peaked only after 5 hours after start of ILP (median: 36.7 ng/ml). In patients with substantial leakage towards systemic circulation, both cytokines peaked higher and earlier as compared with patients with minimal leakage. No correlation was found between cytokine levels and severity of side effects which in all cases were reversible. We conclude that high dose TNF-α infusion in ILP results in extremely high levels of bioactive TNF-α in the systemic circulation without irreversible side effect, and provokes a delayed blood release of large amounts of IL-6; there was a correlation between leakage from the limb during procedure and the magnitude of systemic cytokines levels.
Ferdy J. Lejeune - One of the best experts on this subject based on the ideXlab platform.
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Isolated Perfusion of the limb with high-dose tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and melphalan for melanoma stage III. Results of a multi-centre pilot study.
Melanoma research, 1994Co-Authors: Danielle Lienard, Bbr Kroon, A. M. M. Eggermont, Schraffordt Koops H, Rosenkaimer F, Philippe Autier, Ferdy J. LejeuneAbstract:We report an update of a multi-centre pilot study previously published. Fifty-three patients (42 women, 11 men) were accrued between October 1988 and May 1992: 34 had stage IIIA, 15 had stage IIIAB, and four had stage IV melanoma. Most of them had more than five in-transit metastases; 50% had been previously treated by regional chemotherapy. Protocol included 90-min Isolation Perfusion at 40 degrees C with 2-4 mg rTNF-alpha, 0.2 mg rIFN-gamma and 10/13 mg/l melphalan. We prevented severe TNF systemic side effects by administration of dopamine and fluid loading. There has been no toxic death and the toxicity remained acceptable, with only one multi-organ failure (MOF) and no prolonged shock. Response rates remained very high, with 90% complete remission, 10% partial response and no failure. With a median follow-up time of 26 months, there were 12 regional recurrences, 15 distant metastases and nine local and distant recurrences. The median overall survival has been 28 months. We conclude that high-dose rTNF-alpha associated with melphalan in Isolation Perfusion is the therapy of choice for in-transit melanoma metastases.
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Regional therapy of melanoma.
European Journal of Cancer, 1993Co-Authors: Ferdy J. Lejeune, D. Lienard, Serge Leyvraz, R-o MirimanoffAbstract:Little progress has been made in the systemic treatment of melanoma, that is for disseminated stage IV disease. However, the tumour resistance to therapy, especially chemotherapy can be overcome in melanoma by high doses of anticancer agents administered regionally. The purpose of this paper is to illustrate this concept by two modes of regional treatment namely: (1) Isolation Perfusion of the limbs with high doses of cytokines and chemotherapy under hyperthermia and (2) local treatment of metastatic melanoma. The third part will be devoted to the role of another regional treatment, radiotherapy, where the association with hyperthermy also looks promising.
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In transit metastases of malignant melanoma treated by high dose rTNFα in combination with interferon-γ and melphalan in Isolation Perfusion
World Journal of Surgery, 1992Co-Authors: Danielle Lienard, Ferdy J. Lejeune, Patricia EwalenkoAbstract:To increase the therapeutic efficacy of recombinant tumor necrosis factor alpha (rTNFα) and reduce the systemic side effects, a protocol was designed using Isolation Perfusion of the limbs with hyperthermia for in transit metastases of melanoma. A triple combination of high dose rTNFα + recombinant interferon-gamma (rIFN-γ) + melphalan was chosen because of a synergistic anti-tumor effect of rTNFα with rIFN-γ and of rTNFα with alkylating agents reported in the literature. Twenty-nine patients of mean age 60 years (range 22–82 years) entered the study after informed consent and received a total of 31 Isolation Perfusions with the triple combination. There were 24 women and 5 men with multiple progressive in transit melanoma metastases of the lower limb (stage IIIa or IIIab). rTNFα at the unique dose of 4 mg was injected as a bolus in the arterial line, under mild hyperthermic conditions (40 to 40.5°C) for 90 minutes. rIFN-γ was given subcutaneously on days −2 and −1 and in the perfusate, with rTNFα, at the dose of 0.2 mg. Melphalan was administered in the perfusate at dose giving a concentration of 40 µg/ml. In all the 31 Isolation Perfusions performed in the triple combination protocol, in order to prevent a septic shock-like syndrome which had been encountered in 2 patients treated outside this protocol for sarcoma and carcinoma, the patients received dopamine continuous infusion at 3 µg/kg/min from the start of Isolation Perfusion and for 48 hours, and only showed mild hyptension and very transient chills and temperature. Regional toxicity attributable to rTNFα was minimal. There have been 16 patients with hematologic toxicity consisting of neutropenia (11 cases, 1 case grade 4 and 1 case grade 3) and neutropenia with thrombocytopenia (12 cases, 1 case grade 4 and 4 cases grade 2). Eighteen of 29 patients had been previously treated with melphalan in Isolation Perfusion (n=13) or with cisplatinum (n=2), rTNFα-Melphalan (n=1), or rTNFα alone (n=2). Median follow-up has been 41 weeks. The 29 patients are evaluable: there have been 26 (90%) complete remissions (CR), 3 (10%) partial remissions (PR), and no failures. Actuarial disease-free survival and total survival have been 63% and 73%, respectively, at 12 months. In all cases, softening of the nodules was obvious within 3 days after Isolation Perfusion and time to definite response ranged between day 6 and 22. This interim analysis of a phase II study suggests that high dose of rTNFα can be administered with acceptable toxicity by Isolation Perfusion with dopamine and hyperhydration. Tumor responses can be evidenced in all patients, with 90% CR. Furthermore, combination of rTNFα, rIFN-γ, and melphalan seems to achieve high efficacy with minimal toxicity, even after failure of prior therapy with melphalan alone. Se diseñó un protocolo que utiliza la perfusión aislada de las extremidades con hipertermia a fin de incrementar la eficacia terapéutica del factor necrotizante tumoral alfa recombinante (rFNTα) y reducir sus efectos secundarios sistémicos, en el tratamiento de metástasis en tránsito del melanoma. Se escogió una combinación triple de alta dosis de rFNTα + interferóngamma recombinante (rIFN-γ) + melfalán en virtud del efecto sinergístico antitumoral del rTNFα con el IFN-γ y del rTNFα con los agentes alquilantes informados en la literatura. Veintinueve pacientes con edad promedio de 60 años (rango 22–82) ingresaron al estudio bajo consentimiento informado y recibieron un total de 31 Perfusiones aisladas con la triple combinación. Hubo 24 mujeres y 5 hombres con metástasis en tránsito de melanoma de la extremidad inferior (estado IIa o IIIab). El rTNFα en la dosis única de 4 mg fue inyectado en bolo en la línea arterial, bajo condiciones levemente hipertermicas (40 a 50°C) por 90 minutos. El rIFN-γ fue administrado en los días −2 y −1 en el líquido perfusión, con rTNFα en la dosis de 0.2 mg. El melfalán fue administrado en el líquido de perfusión en una dosis para proveer una concentración de 40 µg/ml. En todos los casos de perfusión aislada en el protocolo de triple combinación, y con el objeto de prevenir un cuadro del tripo de “shock-syndrome” que había sido observado en 2 pacientes tratados por sarcoma y carcinoma por fuera de este protocolo, se administró dopamina en infusión continua a una rata de 3 µg/kg/min desde el comienzo de la pefusión aislada y, por 48 horas; los pacientes sólo exhibieron hipotensión leve y escalofríos y fiebre transitorios. La toxicidad regional atribuible as rTNFα fue mínima. Se han presentado 16 casos con toxicidad hematológica consistente en nuetropenia (11 casos, uno grado 4 y uno grado 3) y neutropenia con trombocitopenia (12 casos, uno grado 4 y cuatro grado 2). Dieciocho de 29 pacientes habían sido previamente tratados con melfalán en perfusión aislada (13/29) o con cisplatino (2/29), rTNFα-melfalán (1/29) or rTNFα solamente (2/29). El promedio del sequimiento fue 41 semanas. Los 29 pacientes son valorables: ha habido 26 remisiones completas (90%), 3 remisiones parciales (10%) y ninguna falla. Las tasas de sobrevida actuarial libre de enfermedad y de sobrevida total han sido 63% y 73%, respectivamente, a 12 meses. En la totalidad de los casos apareció evidente el ablandamiento de los nódulos en los primeros 21 días después de la perfusión aislada y el intervalo hasta la respuesta difinitiva varió entre el día 6 y el día 22. El análisis interim de un estudio de fase II sugiere que la alta dosis de rTNFα puede ser administrada con aceptable toxicidad por perfusión aislada con dopamina e hiperhidratación. Las respuestas tumorales pueden ser evidenciadas en la totalidad de los pacientes, con 90% de remisión completa. Además, la combinación de rTNFα, rIFN-γ y melfalán parece ser de elevada eficacia con toxicidad mínima, aún después de una falla terapéutica con melfalán sólo. Pour augmenter l'efficacité thérapeutique du facteur recombinant de nécrose tumorale alpha (rTNFα) et pour réduire les effets secondaires, on a élaboré un protocole utilisant une Perfusion isolée des extrémités associée à une hyperthermie chez les patients atteints de métastases d'un mélanome. En raison d'un effet synergique antitumoral, de rTNFα et de l'interféron gamma recombinant (rIFN) d'une part et de rTNFα et des agents alkylisants d'autres part (effet rapporté dans la littérature), on a utilisé une triple combinaison de rTNFα à hautes doses, rIFN et melphalan. Vingt neuf patients d'âge moyen de 60 ans (extrêmes 22–82 ans) ont été inclus dans cette étude après avoir donné leur consentement éclairé. Ils ont reçu un total de 31 Perfusions de la tripe association. Il y avait 24 femmes et 5 hommes ayant des métastases multiples extensives des membres inférieurs (stade III a ou II ab). rTNFα a été administré à une dose unique de 4 mg injectée en bolus par voie artérielle, dans des conditions d'hyperthermie modérée (40 à 40.5°C) pendant 90 minutes. rTNFα a été donné en souscutanée aux jours −2 et −1 mélangé à la Perfusion de rTNFα à la dose de 0.2 mg. Le melphalan a été administré à la concentration de 40 mg/ml. Pour éviter un syndrome de choc rencontré chez deux patients traités hors protocole pour sarcome et carcinome, tous les patients de ce protocole ont reçu de la dopamine en Perfusion continue à la dose de 3 µg/kg/mn depuis le début de la Perfusion et pendant 48 heures, et n'ont eu qu'une hypotension modérée avec des frissons transitoires. La toxicité attribuée au rTNFα était minime. On a eu 16 cas de toxicité hématologique comprenant une neutropénie (11 cas, 1 grade 4, 1 grade 3) et neutropénie avec thrombopénie (12 cas, 1 grade 4, 4 grade 2). Dix huit patients avaient déjà été traités par Melphalane en Perfusion isolée (13/39) ou en association avec du cisplatinium (2/29) ou par l'association rTNFα-melphalan (1/29) ou le rTNFα seul (2/29). Le suivi moyen était de 41 semaines. Sur les 29 patients évalués, il y a eu 26 rémissions complètes (RC) (90%), 3 rémissions partielles (RP) (10%) et ancun décès. Les survies actuarielles sans maladie et globale à 12 mois sont respectivement de 63 et de 73%. Dans tous les cas, les nodules se sont assouplis en moins de 3 jours après le début de la Perfusion. Le délai de réponse au traitement variait entre 6 et 22 jours. L'analyse intermédiaire de l'étude de phase II suggère que de fortes doses de rTNFα peuvent être administrées avec une faible toxicité en Perfusion associées à la dopamine et à une hyperhydratation. La réponse tumorale était évidente chez tous les patients avec une CR de 90%. De plus, l'association de rTNFα, IFN et melphalan semble donner une grande efficacité avec une toxicité minime, même en cas d'échec antérieur avec le melphalan utilisé seul.
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High serum levels of TNF-α after its administration for Isolation Perfusion of the limb
Cytokine, 1992Co-Authors: Jean Gerain, Danielle Lienard, Patricia Ewalenko, Ferdy J. LejeuneAbstract:Abstract In a phase II study, 18 patients with locally spreading melanoma or sarcoma of lower limb were treated by Isolation Perfusion (ILP) with hyperthermia and local infusion of high dose of recombinant human tumor necrosis factor α (rHuTNF-α) (4 mg). Bioactive TNF-α and interleukin 6 (IL-6) serum levels were measured serially, In the limb, TNF-α rapidly reached a plateau at 2 μ/ml, while IL-6 appeared later and progressively increased until the end of ILP. In the systemic circulation TNF-α rose up to a median concentration of 31 ng/ml after 1 hour, then decreased and became negligible after 6 hours. IL-6 peaked only after 5 hours after start of ILP (median: 36.7 ng/ml). In patients with substantial leakage towards systemic circulation, both cytokines peaked higher and earlier as compared with patients with minimal leakage. No correlation was found between cytokine levels and severity of side effects which in all cases were reversible. We conclude that high dose TNF-α infusion in ILP results in extremely high levels of bioactive TNF-α in the systemic circulation without irreversible side effect, and provokes a delayed blood release of large amounts of IL-6; there was a correlation between leakage from the limb during procedure and the magnitude of systemic cytokines levels.
Mario Santinami - One of the best experts on this subject based on the ideXlab platform.
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Cardiac and pulmonary effects of alpha tumor necrosis factor administered by Isolation Perfusion.
Tumori, 1995Co-Authors: F. Villani, M. Galimberti, G. Mazzola, I. Stifani, M. Rizzi, Mario Santinami, R. ManziAbstract:AIMS We studied cardiac and pulmonary function in 22 patients affected by in transit metastases from cutaneous melanoma and metastases from soft tissue sarcoma of the limbs and treated with Isolation Perfusion in extracorporeal circulation with rTNF alpha at doses ranging from 0.5 to 4 mg/m2 in mild hyperthermia. PATIENTS AND METHODS All patients experienced a septic-like shock syndrome of variable severity: this feature lasted from 24 to 72 h and was controlled by the infusion of dopamine. Seventeen patients suffered from respiratory insufficiency, which required assisted ventilation (7 cases mechanical ventilation for 1 day, 8 cases for 2 days, and 2 cases synchronized intermittent mandatory ventilation). RESULTS Spirometric parameters recorded 7-15 days after treatment did not change from baseline values. In contrast, lung transfer factor for carbon monoxide significantly declined in a dose dependent fashion. CONCLUSIONS Our data confirm that rTNF alpha administered by Isolation Perfusion technique induces systemic cardiovascular and pulmonary side effects. Further studies are required to better define time course and reversibility of impaired pulmonary function.
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Isolation Perfusion in extracorporeal circulation with interleukin-2 and lymphokine-activated killer cells in the treatment of in-transit metastases from limb cutaneous melanoma.
Annals of surgical oncology, 1995Co-Authors: Maurizio Vaglini, Mario Santinami, Filiberto Belli, Flavio Arienti, Giorgio Parmiani, Laura Persiani, Nicola Santoro, Maria Grazia Inglese, Fortunato D'elia, Natale CascinelliAbstract:Background: Therapies of advanced melanoma patients with interleukin-2 (IL-2) and cytotoxic lymphocytes have produced interesting results, but a larger diffusion of these treatments is limited by the severe side effects due to IL-2 systemic infusion. A strictly regional administration of IL-2 and cells by an Isolation Perfusion (IP) in extracorporeal circulation (ECC) for the treatment of regional melanoma metastases could improve tolerability and efficacy of this specific modality of immunotherapy.
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treatment of primary or relapsing limb cancer by Isolation Perfusion with high dose alpha tumor necrosis factor gamma interferon and melphalan
Cancer, 1994Co-Authors: Maurizio Vaglini, Mario Santinami, Maria Grazia Inglese, M Filiberto D Belli, Mario Ammatuna, M Renato D Manzi, M Augusto D Prada, M Laura D Persiani, M Nicola D Santoro, M Natale D CascinelliAbstract:BACKGROUND Utilization of alpha-tumor necrosis factor (alpha-TNF) in clinical practice is limited by severe general side effects. Very promising results with low toxicity were reported with administration of alpha-TNF by Isolation Perfusion in extracorporeal circulation. METHODS From December 1991 to November 1992, 14 patients underwent Perfusion with alpha-TNF (2-4 mg, total dose), gamma-interferon (1.5 x 10(6) IU), and melphalan (10 mg/l/perfused limb). Twelve patients presented in-transit metastases of the limbs, one patient, a clear cell sarcoma of the hand, and one patient, a wide spindle cell carcinoma of the thigh. Perfusion lasted 90 minutes and was conducted in mild hyperthermia (38-40.5 degrees C, muscle temperature). RESULTS Nine complete regressions and four stable diseases were recorded. In one case, a reliable evaluation of response was not possible for diffused tissue necrosis. Five patients relapsed or progressed locally from 3 to 4 months after surgery, five presented distant localizations from 2 to 7 months after surgery, and one died of disease 6 months after Perfusion. Twelve patients are alive, seven without evidence of disease. A septic-like shock syndrome was observed in all patients and required administration of dopamine, dobutamine, or noradrenaline. One patient died 30 days after Perfusion from a multiorgan-failure syndrome, likely due to alpha-TNF. The follow-up time ranges from 4 to 15 months (median, 6). CONCLUSIONS The preliminary, impressive results reported in other series were not completely confirmed in this study adopting the same treatment scheme. Further clinical experience and biologic data are needed to state the real efficacy of the approach and to reduce the severe general toxicity consistently associated with this type of treatment.
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Treatment of in-transit metastases from cutaneous melanoma by Isolation Perfusion with tumour necrosis factor-alpha (TNF-alpha), melphalan and interferon-gamma (IFN-gamma). Dose-finding experience at the National Cancer Institute of Milan.
Melanoma research, 1994Co-Authors: M. Vaglini, Mario Santinami, R. Manzi, N. Santoro, L. Persiani, Filiberto BelliAbstract:From December 1991 to July 1993, 22 consecutive patients with grade IIIA-IIIAB melanoma underwent Isolation Perfusion with TNF-alpha (0.5-4 mg), melphalan (10 mg/l perfused limb) and, in the first 12 cases, IFN-gamma (1.5 x 10(6) U). The first series of 12 patients received a total dosage TNF-alpha of 2-4 mg, and the second series of 10 cases received an escalating dosage of TNF-alpha (1.5-1.0-0.5 mg) and no IFN-gamma before or during surgery. The Perfusion lasted 90 min and was conducted in mild hyperthermia (39-39.5 degree C muscle temperature). The results of the first series included seven patients in complete remission, four with stable disease and one case not evaluable for local toxicity. Fifty per cent of cases developed a regional relapse from 3 to 4 months after surgery. Presently with a median follow up of 10 months, five patients of this group have no evidence of disease, four are alive with disease, two died from melanoma and one died of complications likely due to treatment (multi-organ failure syndrome). In the second series, the immediate responses included seven patients in complete remission and three in partial remission; with a median follow up of 3 months, two patients developed a regional relapse, respectively, 3 and 5 months after surgery. So far our experience of Perfusion with TNF-alpha has not reproduced the data reported by other investigators. Further clinical and biological findings and a longer follow-up period are needed to draw any conclusion, and a decreasing TNF-alpha dose should be carefully evaluated.
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Treatment of recurrent in transit metastases from cutaneous melanoma by Isolation Perfusion in extracorporeal circulation with interleukin-2 and lymphokine activated killer cells. A pilot study.
Melanoma research, 1992Co-Authors: Filiberto Belli, Mario Santinami, Flavio Arienti, Giorgio Parmiani, Licia Rivoltini, L. Mascheroni, A. Prada, M. Ammatuna, E. Marchesi, Natale CascinelliAbstract:Chemoresistant melanoma cells are known to be susceptible in vitro to lymphokine activated killer (LAK) cells. To obtain a high LAK/tumour cell ratio in vivo and avoid systemic toxicity due to interleukin-2 (IL-2), we used IL-2 plus LAK cells in the treatment of in transit melanoma metastases of the limbs by Isolation Perfusion (IP). In vivo immunological modifications induced by this immunotherapeutic approach were also analysed. Six patients previously treated with IP in extracorporeal circulation with tumour cytotoxic drugs and presently relapsing or not responding, were submitted to locoregional adoptive therapy consisting of 5 days systemic administration of IL-2 (Proleukin, EuroCetus) (9-12 x 10(6) IU/m2/day c.i.). Autologous LAK cells were derived from leukapheresis and subsequent in vitro stimulation with IL-2; LAK cells were then given along with IL-2 (120-2400 IU/ml of Perfusion priming) to the affected limb by IP. In addition, 7-16 x 10(9) LAK cells were administered by systemic infusion the day after together with IL-2 (9-12 x 10(6) IU/m2/day) by c.i. for 5 days. All patients concluded the treatment without major toxicity. The analysis of circulating lymphocytes obtained from extracorporeal circuit at different times revealed rapid disappearance of LAK cells, suggesting their extravasation and/or endothelial adhesion in perfused tissues. Clinical responses included four partial and one complete response; another patient had stable disease. All patients are presently alive. Follow-up after IP ranges from 8 to 22 months.
Ferdy Lejeune - One of the best experts on this subject based on the ideXlab platform.
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Systemic and Hemodynamic Effects of Recombinant Tumor Necrosis Factor Alpha in Isolation Perfusion of the Limbs
Chest, 1995Co-Authors: Philippe Eggimann, Danielle Lienard, Jean Gerain, René Chioléro, Pierre-guy Chassot, Ferdy LejeuneAbstract:Objective To describe the systemic effects of high-dose recombinant tumor necrosis factor alpha (rTNF-α), recombinant interferon gamma (rIFN-γ), and melphalan administered through hyperthermic Isolation Perfusion of the limbs (IPL) in patients with melanoma and malignant soft-tissue tumors. Design The clinical, hemodynamic, and biologic parameters were recorded after IPL during the postoperative period. Setting Surgical intensive care service of a 1,000-bed tertiary university medical center. Patients Nineteen patients referred to a pluridisciplinary Center for Oncology after relapse of regionally advanced melanoma or soft-tissues tumors, included in a phase 2 therapeutic study. Results Major systemic and hemodynamic changes were observed after IPL in all patients. Ninety-four percent (17/18) of the evaluable patients presented a shock unresponsive to fluid challenge, requiring the continuous Perfusion of vasopressors, inotropic agents, or both. Analysis of hemodynamic data showed two distinctive patterns: a pure distributive shock in nine patients requiring norepinephrine, and a mixed distributive and cardiogenic shock in eight patients requiring vasopressor and inotropic agents. The oxygen parameters were characterized by an increase in both the delivery and the uptake of oxygen, with a prolonged reduced oxygen extraction ratio for most patients. The other observed effects were as follows: transient bilateral or mixed pulmonary infiltrates in all patients; some hematologic disturbances in 83% of patients; infection requiring a modification of the antibiotic prophylaxis in 61% of patients; and some liver toxic reactions in 50% of patients. Very high systemic TNF-α serum bioactivity was found in 12 patients for whom serum samples were available, indicating an early and important rTNF-α leakage from the IPL. No correlations could be found between the levels of TNF-α and the observed systemic effects. Despite the severity of the hemodynamic disturbance, no patient died. Conclusion Major systemic effects, consisting mainly in cardiovascular, respiratory, and hematologic disturbances, were observed in patients after IPL with high-dose of rTNF-α. The likely explanation for these observations is an early rTNF-α leakage related to inadequate IPL technique. These data show that the iatrogenic administration of high circulating TNF levels lead to a “septic shock-like” syndrome without resulting in lethal organ dysfunction.
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Administration of high-dose tumor necrosis factor alpha by Isolation Perfusion of the limbs. Rationale and results.
The Journal of infusional chemotherapy, 1995Co-Authors: Ferdy Lejeune, Danielle Lienard, Bbr Kroon, A. M. M. Eggermont, Schraffordt Koops H, Rosenkaimer F, J. Gérain, Klaase J, J. Vanderveken, P SchmitzAbstract:Recombinant tumor necrosis factor alpha (rTNF alpha) has potent antitumor activity in experimental studies on human tumor xenografts. However, in humans, the administration of rTNF alpha is hampered by severe systemic side effects. The maximum tolerated dose ranges from 350 to 500 mg/m2, which is at least 10-fold less than the effective dose in animals. Isolated Perfusion of the limbs (ILP) allows the delivery of high-dose rTNF alpha in a closed system with acceptable side effects. A protocol with a triple-drug regimen was based on the reported synergism of rTNF alpha with chemotherapy, with interferon-gamma, and with hyperthermia. In patients with melanoma-in-transit metastases (stage IIIA or AB), we obtained a 91% complete response rate compared with 52% after ILP with melphalan alone. In unresectable soft tissue sarcomas, this protocol was found to produce a 50% complete response with 87.5% limb salvage, since most tumors became removable. Release of nanograms levels of TNF alpha in the systemic circulation was evident, but control of this leakage and appropriate intensive care resulted in acceptable toxicity. Angiographic, immunohistological, and immunological studies suggest that the efficacy of this protocol is due to a dual targeting: rTNF alpha activates and electively lyses the tumor endothelial cells, while melphalan is mainly cytotoxic to the tumor cells. ILP with rTNF alpha appears to be a useful model for studying the biochemotherapy of cancer in man.
Filiberto Belli - One of the best experts on this subject based on the ideXlab platform.
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Isolation Perfusion in extracorporeal circulation with interleukin-2 and lymphokine-activated killer cells in the treatment of in-transit metastases from limb cutaneous melanoma.
Annals of surgical oncology, 1995Co-Authors: Maurizio Vaglini, Mario Santinami, Filiberto Belli, Flavio Arienti, Giorgio Parmiani, Laura Persiani, Nicola Santoro, Maria Grazia Inglese, Fortunato D'elia, Natale CascinelliAbstract:Background: Therapies of advanced melanoma patients with interleukin-2 (IL-2) and cytotoxic lymphocytes have produced interesting results, but a larger diffusion of these treatments is limited by the severe side effects due to IL-2 systemic infusion. A strictly regional administration of IL-2 and cells by an Isolation Perfusion (IP) in extracorporeal circulation (ECC) for the treatment of regional melanoma metastases could improve tolerability and efficacy of this specific modality of immunotherapy.
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Treatment of in-transit metastases from cutaneous melanoma by Isolation Perfusion with tumour necrosis factor-alpha (TNF-alpha), melphalan and interferon-gamma (IFN-gamma). Dose-finding experience at the National Cancer Institute of Milan.
Melanoma research, 1994Co-Authors: M. Vaglini, Mario Santinami, R. Manzi, N. Santoro, L. Persiani, Filiberto BelliAbstract:From December 1991 to July 1993, 22 consecutive patients with grade IIIA-IIIAB melanoma underwent Isolation Perfusion with TNF-alpha (0.5-4 mg), melphalan (10 mg/l perfused limb) and, in the first 12 cases, IFN-gamma (1.5 x 10(6) U). The first series of 12 patients received a total dosage TNF-alpha of 2-4 mg, and the second series of 10 cases received an escalating dosage of TNF-alpha (1.5-1.0-0.5 mg) and no IFN-gamma before or during surgery. The Perfusion lasted 90 min and was conducted in mild hyperthermia (39-39.5 degree C muscle temperature). The results of the first series included seven patients in complete remission, four with stable disease and one case not evaluable for local toxicity. Fifty per cent of cases developed a regional relapse from 3 to 4 months after surgery. Presently with a median follow up of 10 months, five patients of this group have no evidence of disease, four are alive with disease, two died from melanoma and one died of complications likely due to treatment (multi-organ failure syndrome). In the second series, the immediate responses included seven patients in complete remission and three in partial remission; with a median follow up of 3 months, two patients developed a regional relapse, respectively, 3 and 5 months after surgery. So far our experience of Perfusion with TNF-alpha has not reproduced the data reported by other investigators. Further clinical and biological findings and a longer follow-up period are needed to draw any conclusion, and a decreasing TNF-alpha dose should be carefully evaluated.
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Treatment of recurrent in transit metastases from cutaneous melanoma by Isolation Perfusion in extracorporeal circulation with interleukin-2 and lymphokine activated killer cells. A pilot study.
Melanoma research, 1992Co-Authors: Filiberto Belli, Mario Santinami, Flavio Arienti, Giorgio Parmiani, Licia Rivoltini, L. Mascheroni, A. Prada, M. Ammatuna, E. Marchesi, Natale CascinelliAbstract:Chemoresistant melanoma cells are known to be susceptible in vitro to lymphokine activated killer (LAK) cells. To obtain a high LAK/tumour cell ratio in vivo and avoid systemic toxicity due to interleukin-2 (IL-2), we used IL-2 plus LAK cells in the treatment of in transit melanoma metastases of the limbs by Isolation Perfusion (IP). In vivo immunological modifications induced by this immunotherapeutic approach were also analysed. Six patients previously treated with IP in extracorporeal circulation with tumour cytotoxic drugs and presently relapsing or not responding, were submitted to locoregional adoptive therapy consisting of 5 days systemic administration of IL-2 (Proleukin, EuroCetus) (9-12 x 10(6) IU/m2/day c.i.). Autologous LAK cells were derived from leukapheresis and subsequent in vitro stimulation with IL-2; LAK cells were then given along with IL-2 (120-2400 IU/ml of Perfusion priming) to the affected limb by IP. In addition, 7-16 x 10(9) LAK cells were administered by systemic infusion the day after together with IL-2 (9-12 x 10(6) IU/m2/day) by c.i. for 5 days. All patients concluded the treatment without major toxicity. The analysis of circulating lymphocytes obtained from extracorporeal circuit at different times revealed rapid disappearance of LAK cells, suggesting their extravasation and/or endothelial adhesion in perfused tissues. Clinical responses included four partial and one complete response; another patient had stable disease. All patients are presently alive. Follow-up after IP ranges from 8 to 22 months.
