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World Journal of Surgery

, Volume 16, Issue 2, pp 234–240 | Cite as

In transit metastases of malignant melanoma treated by high dose rTNFα in combination with interferon-γ and melphalan in isolation perfusion

  • Danielle Liénard
  • Ferdy J. Lejeune
  • Patricia Ewalenko
World Progress In Surgery

Abstract

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 progressivein 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.

Keywords

Melanoma Melphalan Triple Combination Case Grade Recombinant Tumor Necrosis Factor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Résumé

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.

Resumen

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.

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Copyright information

© the Société Internationale de Chirurgie 1992

Authors and Affiliations

  • Danielle Liénard
    • 1
  • Ferdy J. Lejeune
    • 1
  • Patricia Ewalenko
    • 1
  1. 1.Laboratory of Oncology and Experimental Surgery, Melanoma and Sarcoma Clinic, Department of Surgery, and Department of Anaesthesiology, Jules Bordet InstituteUniversité Libre de BruxellesBelgium

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