Rationale for different approaches to combined melphalan and hyperthermia in regional isolated perfusion

The addition of hyperthermia (HT) to regional isolated perfusion (RIP) with Melphalan theoretically has two advantages. Firstly, heat can selectively kill cells in poorly vascularised areas that are usually not reached by the drug. Secondly, in vitro data have revealed that the effect of Melphalan is enhanced at temperatures 39-45 degrees C. However, for the simultaneous application of Melphalan and HT, as it is given in most institutes, both normal and tumour tissues within the volume are treated with both modalities. It is unclear whether-for the same heat dose-the cytoxicity of Melphalan is enhanced more in tumour tissue than in normal tissues. As the applied dose of Melphalan in RIP is selected on maximum acceptable toxicity, any enhancement of toxicity is undesired. Indeed, Melphalan application at temperatures >41 degrees C has resulted in unacceptable toxicity. In most institutes, the hyperthermia dose is reduced in comparison to application as a single-modality treatment, to allow simultaneous combination without unacceptable toxicity. In this review, the rationale for two different approaches is summarised which may make it possible to improve the benefit from the theoretical advantage of the use of HT in RIP. It is meant to stimulate discussion as a possible first step in the design of new treatment protocols. (C) 1997 Elsevier Science Ltd

VWF release and platelet aggregation in human melanoma after perfusion with TNFα

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. Copyright © 1995 John Wiley & Sons, Ltd.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity sarcomas: The cumulative multicenter European experience

Objective: The objective of the study was to achieve limb salvage in patients with locally advanced soft tissue sarcomas that can only be treated by amputation or functionally mutilating surgery by performing an isolated limb perfusion (ILP) with tumor necrosis factor (TNF) + melphalan (M) as induction biochemotherapy to obtain local control and make limb-sparing surgery possible. Summary Background Data: To increase the number of limb- sparing resections in the treatment of locally advanced extremity soft tissue sarcoma, preoperative radiation therapy or chemotherapy or a combination of the two often are applied. The ILP with cytostatic agents alone is another option but rarely is used because of rather poor results. The efficacy of the application of TNF in ILP markedly has changed this situation. Methods: In 8 cancer centers, 186 patients were treated over a period of almost 4.5 years. There were 107 (57%) primary and 79 (43%) recurrent sarcomas, mostly high grade (110 grade III; 51 grade II; and 25 very large, recurrent, or multiple grade I sarcomas). The composition of this series of patients is unusual: 42 patients (23%) had multifocal primary or multiple recurrent tumors; median tumor size was very large (16 cm); 25 patients (13%) had known systemic metastases at the time of the ILP. Patients underwent a 90-minute ILP at 39 to 40 C with TNF + melphalan. The first 55 patients also received interferon- τ. A delayed marginal resection of the tumor remnant was done 2 to 4 months after ILP. Results: A major tumor response was seen in 82% of the patients rendering these large sarcomas resectable in most cases. Clinical response rates were: 33 complete response (CR) (18%), 106 partial response (PR) (57%), 42 no change (NC) (22%), and 5 progressive disease (PD) (3%). Final outcome was defined by clinical and pathologic response: 54 CR (29%), 99 PR (53%), 29 NC (16%), and 4 PD (2%). At a median follow up of almost 2 years (22 months; range, 6-58 months), limb salvage was achieved in 82%. Regional toxicity was limited and systemic toxicity minimal to moderate, easily managed, with no toxic deaths. Conclusions: In the setting of isolated limb perfusion, TNF is an active anticancer drug in patients. The ILP with TNF + melphalan can be performed safely in many centers and is an effective induction treatment with a high response rate that can achieve limb salvage in patients with locally advanced extremity soft tissue sarcoma.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Thin Stage I Primary Cutaneous Malignant Melanoma

Although wide surgical excision is the accepted treatment for thin malignant melanomas, there is reason to believe that narrower margins may be adequate. We conducted a randomized prospective study to assess the efficacy of narrow excision (excision with 1-cm margins) for primary melanomas no thicker than 2 mm. Narrow excision was performed in 305 patients, and wide excision (margins of 3 cm or more) was performed in 307 patients. The major prognostic criteria were well balanced in the two groups. The mean thickness of melanomas was 0.99 mm in the narrow-excision group and 1.02 mm in the wide-excision group. The subsequent development of metastatic disease involving regional nodes and distant organs was not different in the two groups (4.6 and 2.3 percent, respectively, in the narrow-excision group, as compared with 6.5 and 2.6 percent in the wide-excision group). Disease-free survival rates and overall survival rates (mean follow-up period, 55 months) were also similar in the two groups. Only three patients had a local recurrence as a first relapse. All had undergone narrow excision, and each had a primary melanoma with a thickness of 1 mm or more. The absence of local recurrence in the group of patients with a primary melanoma thinner than 1 mm and the very low rate of local recurrences indicate that narrow excision is a safe and effective procedure for such patients. (N Engl J Med 1988; 318:1159–62.) THE question of how much surrounding normal skin should be removed during the excision of primary melanomas of the skin has never been properly answered. For decades, wide excision (with margins of 3 to 5 cm) has been universally accepted as the treatment of choice. In 1977, however, Breslow and Macht1 reported that narrow resection margins may be satisfactory in the treatment of very thin melanomas. Subsequent reports2 3 4 5 6 7 8 9 10 11 have also supported the conservative surgical approach to local control of the primary tumor. Nevertheless, there are several points of disagreement, including how thick a primary melanoma can be and still be. © 1988, Massachusetts Medical Society. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe