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Melanoma research 12/2012; 22(6):413-4. · 2.06 Impact Factor
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Stéphane Cherix,
Mélanie Speiser,
Maurice Matter,
Wassim Raffoul,
Danièle Liénard,
Nicolas Theumann,
Elyazid Mouhsine,
René-Olivier Mirimanoff,
Serge Leyvraz, Ferdy J Lejeune,
Pierre-François Leyvraz
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ABSTRACT: Isolated limb perfusion with TNF-alpha and melphalan (TM-ILP) is a limb salvage therapy for non-resectable soft tissue sarcomas (STS) of the extremities. It is indicated for patients for whom amputation or debilitating surgery is the only alternative. It can be used either as an exclusive therapy (in palliation) or as a neo-adjuvant treatment, followed by marginal resection of tumor remnants with minimal functional impairment.
Between February 1992 and March 2006, 57 TM-ILPs were performed on 51 patients with 88% high grade and 84% advanced stage tumors.
Mean follow-up is 38.9 months (4-159, median 22 months). Twenty-one percent patients had significant early complications, with 3 major re-operations, and 23% suffered long-lasting complications. Complete response was observed in 25%, partial response in 42%, stable disease in 14% and progressive disease in 14%. Resection of the tumor remnants was possible in 65%. A complementary treatment was necessary in 31%, mostly radiation therapy. A local recurrence was observed in 35%, after a mean of 20.3 months (2-78), and distant relapse was seen in 45%, after a mean of 13.4 months (5-196). Mean Disease-free survival was 14.9 months, and overall 5-year-survival 43.5%. Amputation rate at 5 years was 24%.
TM-ILP is a conservative treatment with a high complications rate, but it can be successful even for the most severe STS of extremities. As a consequence the limb can be spared from amputation or debilitating surgery on the long term in about 75% of patients.
Journal of Surgical Oncology 10/2008; 98(3):148-55. · 2.10 Impact Factor
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10/2007: pages 230 - 237; , ISBN: 9780470987346
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ABSTRACT: Classical metastatic melanoma therapy is disappointing but important progress has been made in the understanding of melanoma biology. Genetic lesions and several intracellular signaling pathways that could serve as targets for novel therapy have been identified and a number of new agents are under evaluation. Promising tumor cell targets were identified in the cell membrane, cytoplasm and nucleus. New therapeutic approaches, besides monoclonal antibodies and vaccination, include an increasing number of small molecules that have been shown to interfere restrictively with intracellular signaling pathways in melanoma and decrease proliferation, survival, migration or invasion. Other agents can interfere with stromal components of melanoma, such as angiogenesis and components of the immune system.
Expert Review of Anti-infective Therapy 06/2007; 7(5):701-13. · 2.65 Impact Factor
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Journal of Clinical Oncology 05/2007; 25(11):1449-50; author reply 1450-1. · 18.37 Impact Factor
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Ferdy J Lejeune
Melanoma Research 11/2006; 16(5):377-8. · 2.19 Impact Factor
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ABSTRACT: Experimental and clinical evidence indicates that non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors may have anti-cancer activities. Here we report on a patient with a metastatic melanoma of the leg who experienced a complete and sustained regression of skin metastases upon continuous single treatment with the cyclooxygenase-2 inhibitor rofecoxib. Our observations indicate that the inhibition of cyclooxygenase-2 can lead to the regression of disseminated skin melanoma metastases, even after failure of chemotherapy.
Melanoma Research 07/2006; 16(3):263-5. · 2.19 Impact Factor
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ABSTRACT: The formation of a 'tumor-associated vasculature', a process referred to as tumor angiogenesis, is a stromal reaction essential for tumor progression. Inhibition of tumor angiogenesis suppresses tumor growth in many experimental models, thereby indicating that tumor-associated vasculature may be a relevant target to inhibit tumor progression. Among the antiangiogenic molecules reported to date many are peptides and proteins. They include cytokines, chemokines, antibodies to vascular growth factors and growth factor receptors, soluble receptors, fragments derived from extracellular matrix proteins and small synthetic peptides. The polypeptide tumor necrosis factor (TNF, Beromun) was the first drug registered for the regional treatment of human cancer, whose mechanisms of action involved selective disruption of the tumor vasculature. More recently, bevacizumab (Avastin), an antibody against vascular endothelial growth factor (VEGF)-A, was approved as the first systemic antiangiogenic drug that had a significant impact on the survival of patients with advanced colorectal cancer, in combination with chemotherapy. Several additional peptides and antibodies with antiangiogenic activity are currently tested in clinical trials for their therapeutic efficacy. Thus, peptides, polypeptides and antibodies are emerging as leading molecules among the plethora of compounds with antiangiogenic activity. In this article, we will review some of these molecules and discuss their mechanism of action and their potential therapeutic use as anticancer agents in humans.
Biochimica et Biophysica Acta 05/2006; 1765(2):155-77. · 4.66 Impact Factor
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Ferdy J Lejeune
Melanoma Research 03/2006; 16(1):1-2. · 2.19 Impact Factor
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ABSTRACT: Recombinant human tumour necrosis factor (TNF) has a selective effect on angiogenic vessels in tumours. Given that it induces vasoplegia, its clinical use has been limited to administration through isolated limb perfusion (ILP) for regionally advanced melanomas and soft tissue sarcomas of the limbs. When combined with the alkylating agent melphalan, a single ILP produces a very high objective response rate. In melanoma, the complete response (CR) rate is around 80% and the overall objective response rate greater than 90%. In soft tissue sarcomas that are inextirpable, ILP is a neoadjuvant treatment resulting in limb salvage in 80% of the cases. The CR rate averages 20% and the objective response rate is around 80%. The mode of action of TNF-based ILP involves two distinct and successive effects on the tumour-associated vasculature: first, an increase in endothelium permeability leading to improved chemotherapy penetration within the tumour tissue, and second, a selective killing of angiogenic endothelial cells resulting in tumour vessel destruction. The mechanism whereby these events occur involves rapid (of the order of minutes) perturbation of cell-cell adhesive junctions and inhibition of alphavbeta3 integrin signalling in tumour-associated vessels, followed by massive death of endothelial cells and tumour vascular collapse 24 hours later. New, promising approaches for the systemic use of TNF in cancer therapy include TNF targeting by means of single chain antibodies or endothelial cell ligands, or combined administration with drugs perturbing integrin-dependent signalling and sensitizing angiogenic endothelial cells to TNF-induced death.
Cancer immunity: a journal of the Academy of Cancer Immunology 02/2006; 6:6.
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Donata Rimoldi,
Robert Lemoine,
Anne-Marie Kurt,
Suzanne Salvi,
Magali Berset,
Maurice Matter,
Bruno Roche,
Jean-Philippe Cerottini,
David Guggisberg,
Joachim Krischer,
Ralph Braun,
Jean-Pierre Willi,
Christian Antonescu,
Daniel Slosman, Ferdy J Lejeune,
Danielle Liénard
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ABSTRACT: The technique of sentinel lymph node (SLN) dissection is a reliable predictor of metastatic disease in the lymphatic basin draining the primary melanoma. Reverse transcription-polymerase chain reaction (RT-PCR) is emerging as a highly sensitive technique to detect micrometastases in SLNs, but its specificity has been questioned. A prospective SLN study in melanoma patients was undertaken to compare in detail immunopathological versus molecular detection methods. Sentinel lymphadenectomy was performed on 57 patients, with a total of 71 SLNs analysed. SLNs were cut in slices, which were alternatively subjected to parallel multimarker analysis by microscopy (haematoxylin and eosin and immunohistochemistry for HMB-45, S100, tyrosinase and Melan-A/MART-1) and RT-PCR (for tyrosinase and Melan-A/MART-1). Metastases were detected by both methods in 23% of the SLNs (28% of the patients). The combined use of Melan-A/MART-1 and tyrosinase amplification increased the sensitivity of PCR detection of microscopically proven micrometastases. Of the 55 immunopathologically negative SLNs, 25 were found to be positive on RT-PCR. Notably, eight of these SLNs contained naevi, all of which were positive for tyrosinase and/or Melan-A/MART-1, as detected at both mRNA and protein level. The remaining 41% of the SLNs were negative on both immunohistochemistry and RT-PCR. Analysis of a series of adjacent non-SLNs by RT-PCR confirmed the concept of orderly progression of metastasis. Clinical follow-up showed disease recurrence in 12% of the RT-PCR-positive immunopathology-negative SLNs, indicating that even an extensive immunohistochemical analysis may underestimate the presence of micrometastases. However, molecular analyses, albeit more sensitive, need to be further improved in order to attain acceptable specificity before they can be applied diagnostically.
Melanoma Research 11/2003; 13(5):511-20. · 2.19 Impact Factor
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Donata Rimoldi,
Robert Lemoine,
Anne-Marie Kurt,
Suzanne Salvi,
Magali Berset,
Maurice Matter,
Bruno Roche,
Jean-Philippe Cerottini,
David Guggisberg,
Joachim Krischer,
Ralph Braun,
Jean-Pierre Willi,
Christian Antonescu,
Daniel Slosman, Ferdy J Lejeune,
Danielle Liénard,
for the Groupe Mélanome Lémanique
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ABSTRACT: The technique of sentinel lymph node (SLN) dissection is a reliable predictor of metastatic disease in the lymphatic basin draining the primary melanoma. Reverse transcription-polymerase chain reaction (RT-PCR) is emerging as a highly sensitive technique to detect micrometastases in SLNs, but its specificity has been questioned. A prospective SLN study in melanoma patients was undertaken to compare in detail immunopathological versus molecular detection methods. Sentinel lymphadenectomy was performed on 57 patients, with a total of 71 SLNs analysed. SLNs were cut in slices, which were alternatively subjected to parallel multimarker analysis by microscopy (haematoxylin and eosin and immunohistochemistry for HMB-45, S100, tyrosinase and Melan-A/MART-1) and RT-PCR (for tyrosinase and Melan-A/MART-1). Metastases were detected by both methods in 23% of the SLNs (28% of the patients). The combined use of Melan-A/MART-1 and tyrosinase amplification increased the sensitivity of PCR detection of microscopically proven micrometastases. Of the 55 immunopathologically negative SLNs, 25 were found to be positive on RT-PCR. Notably, eight of these SLNs contained naevi, all of which were positive for tyrosinase and/or Melan-A/MART-1, as detected at both mRNA and protein level. The remaining 41% of the SLNs were negative on both immunohistochemistry and RT-PCR. Analysis of a series of adjacent non-SLNs by RT-PCR confirmed the concept of orderly progression of metastasis. Clinical follow-up showed disease recurrence in 12% of the RT-PCR-positive immunopathology-negative SLNs, indicating that even an extensive immunohistochemical analysis may underestimate the presence of micrometastases. However, molecular analyses, albeit more sensitive, need to be further improved in order to attain acceptable specificity before they can be applied diagnostically.
Melanoma Research 09/2003; 13(5):511-520. · 2.19 Impact Factor
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ABSTRACT: RAF proteins are serine/threonine kinases that mediate cellular responses to growth signals by activating the mitogen-activated protein kinase pathway. Mutations in the BRAF gene causing a V599E amino acid substitution that enhance the kinase activity have been described in >60% of cutaneous melanomas and premalignant melanocytic lesions. We have investigated the frequency of BRAF mutations at the expression level in melanomas of the uveal tract. None of the 30 metastases and 10 primary uveal melanomas tested expressed the V599E mutation. In contrast, this mutation was expressed by 65% of cutaneous melanoma samples, confirming previous results. In addition, a double mutation resulting in V599K substitution was detected in two suspect ocular metastases of cutaneous melanoma. Analysis of exon 11, the second common site of BRAF mutations, revealed only wild-type sequences in uveal melanomas. Analysis of tumor lysates showed the presence of phosphorylated mitogen-activated protein kinase, kinase, and mitogen-activated protein kinase in 50% of uveal and 100% of cutaneous melanoma metastases. Taken together, these results suggest that although the common BRAF mutations found in cutaneous melanoma do not play a role in tumorigenesis of uveal tract melanocytes, activation of the RAF/mitogen-activated protein kinase pathway may nevertheless play an important role in uveal melanoma.
Cancer Research 09/2003; 63(18):5712-5. · 7.86 Impact Factor
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02/2003: pages 40 - 55; , ISBN: 9783527600793
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ABSTRACT: Recent evidence indicates that tumor response rates after isolated limb perfusion (ILP) are improved when tumor necrosis factor (TNF) is added to the locoregional perfusion of high doses of chemotherapy. Other factors, related to the patient or the ILP procedure, may interfere with the specific role of TNF in the early hemodynamic response after ILP with TNF and high-dose chemotherapy.
Case-control study.
Tertiary care university hospital.
Thirty-eight patients with a locoregionally advanced tumor of a limb treated by ILP with TNF and high-dose chemotherapy (TNF group) were compared with 31 similar patients treated by ILP with high-dose chemotherapy alone (non-TNF group).
Swan-Ganz catheter hemodynamic recordings, patients' treatment data collection, and TNF and interleukin 6 plasma level measurements at regular intervals during the first 36 hours following ILP.
Hemodynamic profile and total fluid and catecholamine administration.
In the TNF group, significant changes were observed (P<.006): the mean arterial pressure and the systemic vascular resistance index decreased, and the temperature, heart rate, and cardiac index increased. These hemodynamic alterations started when the ILP tourniquet was released (ie, when or shortly after the systemic TNF levels were the highest). The minimal mean arterial pressure, the minimal systemic vascular resistance index, the maximal cardiac index, the intensive care unit stay, and the interleukin 6 maximal systemic levels were significantly (P<.001 for all) correlated to the log(10) of the systemic TNF level. In the non-TNF group, only a brief decrease in the blood pressure following tourniquet release and an increase in the temperature and in the heart rate were statistically significant (P<.006). Despite significantly more fluid and catecholamine administration in the TNF group, the mean arterial pressure and the systemic vascular resistance index were significantly (P<.001) lower than in the non-TNF group.
Release of the tourniquet induces a blood pressure decrease that lasts less than 1 hour in the absence of TNF and that is distinct from the septic shock-like hemodynamic profile following TNF administration. The systemic TNF levels are correlated to this hemodynamic response, which can be observed even at low TNF levels.
Archives of Surgery 01/2003; 138(1):17-25. · 4.24 Impact Factor
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Ferdy J Lejeune
Journal of Clinical Investigation 09/2002; 110(4):433-5. · 15.39 Impact Factor
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Ferdy J Lejeune
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ABSTRACT: Skin melanoma, unlike other cancers, occurs on the body surface: it can be detected and treated before it reaches the stage where it can metastasise; the impact of surgery is unrivalled, but only while it is at this early stage. In melanomas more than 0.75-1.00 mm thick, an increasing proportion acquire metastatic properties. There is today evidence showing that wide excision does not help, and that the effect of surgery is limited to local control of the disease. According to randomised trials, the territory of early spread--without concomitant distant micrometastases--that can be eradicated by surgery is shrinking. It has been demonstrated that resection margins of 3-4 cm are no better in terms of recurrence and survival than margins of 1 or 2 cm. Most melanomas can now be adequately resected without skin grafting. Regional elective lymph node dissection for high-risk melanoma (1.5 mm thick or more) does not improve survival over that obtained with delayed lymph node dissection performed when clinical metastases appear. By analogy, prophylactic isolated limb perfusion with melphalan reduces the rate of in-transit metastases but does not improve survival. Sentinel node biopsy allows early detection of regional lymph node metastases with minimally invasive surgery. On-going randomised studies will show whether it can have any impact on survival. Considering the experience with elective lymph node dissection, it seems unlikely that selective--as opposed to elective--lymph node dissection, of positive sentinel nodes, will influence survival. The already extensive experience with sentinel node biopsy provides a death risk hierarchy: one N2 node (with clinical metastasis), one N1 node--or sentinel node--with micrometastasis and one N0 node with no histologically detectable micrometastasis but PCR positive give, respectively, 50%, 60% and 70% 5-year survival rates. In other words, the earlier the detection of metastasis, the longer the survival. In terms of growth kinetics, the earlier the detection of metastasis, the longer the time to death, with no evidence that surgery would have an impact. There is just one, as yet unpredictable, subset of pa- tients with lymph node-confined disease in whom surgery might have an impact. It is hoped that, in the future, gene expression profiles of primary melanoma will help to pick out these patients. Multivariate analysis has shown that the sentinel node status is the most powerful prognostic factor in primary melanoma. Sentinel node biopsy is a valuable tool for selecting patients for adjuvant treatments within the frame of clinical trials, in which micrometastatic and clinically involved lymph nodes are entered separately. In-transit metastases can be eradicated in 50% of cases by isolated limb perfusion with melphalan under mild hyperthermia. When in-transit metastases are recurrent, deep seated, or bulky, the combination of tumour necrosis factor (TNF) with melphalan and interferon gamma yields a complete response rate of around 80%. This is the first antiangiogenic treatment of cancer that is effective in clinical practice, but it has no effect on survival. Current better knowledge of melanoma biology indicates that local, limited surgery has an impact on local or regional spread only.
Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 02/2002; 160:151-7.
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ABSTRACT: Twenty-nine stage IIIA/B melanoma patients treated by isolated limb perfusion (ILP) with a high dose of recombinant human tumour necrosis factor alpha (rHuTNFα), interferon γ (IFNγ), and melphalan were histologically documented with emphasis on therapy-induced changes of the tumour vasculature. Sequential biopsies were taken at various intervals before and after the treatment to compare the morphological changes. In order to visualize microvascular changes, immunostaining was performed for von Willebrand factor (VWF), type IV collagen, α-smooth muscle actin, endothelial antigen PAL-E, tissue factor, CD41 (thrombocyte marker), and fibrin. In biopsies prior to perfusion, necrosis, haemorrhage, and fibrin thrombi were not found. Within 3 h following triple combination therapy, a change in the distribution of VWF staining occurred, from a discrete endothelial pattern in the untreated lesions to a fuzzy perivascular and subepidermal pattern in the treated lesions. Within 24 h, this was accompanied by intravascular thrombocyte aggregation and erythrostasis, in the absence of tissue factor and fibrin deposits. These findings indicate that the thrombocyte aggregation observed is not caused by local procoagulant activity, but is rather the result of the therapy-associated vascular damage or haemostasis. Although it is difficult to derive the dynamics of this process from static images, we assume that TNFα induced endothelial cell damage, leading to VWF release. Released VWF may play a role in the adhesion between thrombocytes and the damaged endothelium or the denuded subendothelium. As a consequence, the blood flow is impaired, leading to congestion and oedema, compatible with an early stage of haemorrhagic infarction.
The Journal of Pathology 06/1995; 176(3):279 - 287. · 6.32 Impact Factor
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ABSTRACT: To increase the therapeutic efficacy of recombinant tumor necrosis factor alpha (rTNF) 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 rTNF + recombinant interferon-gamma (rIFN-) + melphalan was chosen because of a synergistic anti-tumor effect of rTNF with rIFN- and of rTNF 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). rTNF at the unique dose of 4 mg was injected as a bolus in the arterial line, under mild hyperthermic conditions (40 to 40.5C) for 90 minutes. rIFN- was given subcutaneously on days –2 and –1 and in the perfusate, with rTNF, at the dose of 0.2 mg. Melphalan was administered in the perfusate at dose giving a concentration of 40 g/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 g/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 rTNF 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), rTNF-Melphalan (n=1), or rTNF 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 rTNF 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 rTNF, rIFN-, and melphalan seems to achieve high efficacy with minimal toxicity, even after failure of prior therapy with melphalan alone.Se dise un protocolo que utiliza la perfusin aislada de las extremidades con hipertermia a fin de incrementar la eficacia teraputica del factor necrotizante tumoral alfa recombinante (rFNT) y reducir sus efectos secundarios sistmicos, en el tratamiento de metstasis en trnsito del melanoma. Se escogi una combinacin triple de alta dosis de rFNT + interferngamma recombinante (rIFN-) + melfaln en virtud del efecto sinergstico antitumoral del rTNF con el IFN- y del rTNF con los agentes alquilantes informados en la literatura. Veintinueve pacientes con edad promedio de 60 aos (rango 22–82) ingresaron al estudio bajo consentimiento informado y recibieron un total de 31 perfusiones aisladas con la triple combinacin. Hubo 24 mujeres y 5 hombres con metstasis en trnsito de melanoma de la extremidad inferior (estado IIa o IIIab). El rTNF en la dosis nica de 4 mg fue inyectado en bolo en la lnea arterial, bajo condiciones levemente hipertermicas (40 a 50C) por 90 minutos. El rIFN- fue administrado en los das –2 y –1 en el lquido perfusin, con rTNF en la dosis de 0.2 mg. El melfaln fue administrado en el lquido de perfusin en una dosis para proveer una concentracin de 40 g/ml.En todos los casos de perfusin aislada en el protocolo de triple combinacin, y con el objeto de prevenir un cuadro del tripo de shock-syndrome que haba sido observado en 2 pacientes tratados por sarcoma y carcinoma por fuera de este protocolo, se administr dopamina en infusin continua a una rata de 3 g/kg/min desde el comienzo de la pefusin aislada y, por 48 horas; los pacientes slo exhibieron hipotensin leve y escalofros y fiebre transitorios. La toxicidad regional atribuible as rTNF fue mnima. Se han presentado 16 casos con toxicidad hematolgica 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 haban sido previamente tratados con melfaln en perfusin aislada (13/29) o con cisplatino (2/29), rTNF-melfaln (1/29) or rTNF 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 apareci evidente el ablandamiento de los ndulos en los primeros 21 das despus de la perfusin aislada y el intervalo hasta la respuesta difinitiva vari entre el da 6 y el da 22.El anlisis interim de un estudio de fase II sugiere que la alta dosis de rTNF puede ser administrada con aceptable toxicidad por perfusin aislada con dopamina e hiperhidratacin. Las respuestas tumorales pueden ser evidenciadas en la totalidad de los pacientes, con 90% de remisin completa. Adems, la combinacin de rTNF, rIFN- y melfaln parece ser de elevada eficacia con toxicidad mnima, an despus de una falla teraputica con melfaln slo.Pour augmenter l'efficacit thrapeutique du facteur recombinant de ncrose tumorale alpha (rTNF) et pour rduire les effets secondaires, on a labor un protocole utilisant une perfusion isole des extrmits associe une hyperthermie chez les patients atteints de mtastases d'un mlanome. En raison d'un effet synergique antitumoral, de rTNF et de l'interfron gamma recombinant (rIFN) d'une part et de rTNF et des agents alkylisants d'autres part (effet rapport dans la littrature), on a utilis une triple combinaison de rTNF hautes doses, rIFN et melphalan. Vingt neuf patients d'ge moyen de 60 ans (extrmes 22–82 ans) ont t inclus dans cette tude aprs avoir donn leur consentement clair. Ils ont reu un total de 31 perfusions de la tripe association. Il y avait 24 femmes et 5 hommes ayant des mtastases multiples extensives des membres infrieurs (stade III a ou II ab). rTNF a t administr une dose unique de 4 mg injecte en bolus par voie artrielle, dans des conditions d'hyperthermie modre (40 40.5C) pendant 90 minutes. rTNF a t donn en souscutane aux jours –2 et –1 mlang la perfusion de rTNF la dose de 0.2 mg. Le melphalan a t administr la concentration de 40 mg/ml. Pour viter un syndrome de choc rencontr chez deux patients traits hors protocole pour sarcome et carcinome, tous les patients de ce protocole ont reu de la dopamine en perfusion continue la dose de 3 g/kg/mn depuis le dbut de la perfusion et pendant 48 heures, et n'ont eu qu'une hypotension modre avec des frissons transitoires. La toxicit attribue au rTNF tait minime. On a eu 16 cas de toxicit hmatologique comprenant une neutropnie (11 cas, 1 grade 4, 1 grade 3) et neutropnie avec thrombopnie (12 cas, 1 grade 4, 4 grade 2). Dix huit patients avaient dj t traits par Melphalane en perfusion isole (13/39) ou en association avec du cisplatinium (2/29) ou par l'association rTNF-melphalan (1/29) ou le rTNF seul (2/29). Le suivi moyen tait de 41 semaines. Sur les 29 patients valus, il y a eu 26 rmissions compltes (RC) (90%), 3 rmissions partielles (RP) (10%) et ancun dcs. Les survies actuarielles sans maladie et globale 12 mois sont respectivement de 63 et de 73%. Dans tous les cas, les nodules se sont assouplis en moins de 3 jours aprs le dbut de la perfusion. Le dlai de rponse au traitement variait entre 6 et 22 jours. L'analyse intermdiaire de l'tude de phase II suggre que de fortes doses de rTNF peuvent tre administres avec une faible toxicit en perfusion associes la dopamine et une hyperhydratation. La rponse tumorale tait vidente chez tous les patients avec une CR de 90%. De plus, l'association de rTNF, IFN et melphalan semble donner une grande efficacit avec une toxicit minime, mme en cas d'chec antrieur avec le melphalan utilis seul.
World Journal of Surgery 02/1992; 16(2):234-240. · 2.36 Impact Factor
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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.
Cytokine.
