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Hyperthermic Isolated Limb Perfusion With Tumor Necrosis Factor Is a Useful Therapy for Advanced Melanoma of the Limbs

Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

Alexander M.M. Eggermont

Erasmus University Medical Center, Rotterdam, the Netherlands

To the Editor:

Cornett et al¹ reported the results of a randomized multicenter trial on hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor (TNF) comparing melphalan alone with melphalan plus TNF for locally advanced extremity melanoma. In the abstract, the authors concluded that the addition of TNF to melphalan did not demonstrate a significant enhancement of short-term response rates over melphalan alone. This conclusion is based on the per-protocol evaluation of the responses, but without reading the whole article, the reader could be mislead and consider that TNF has no role in limb perfusion. The primary end point of the trial raises some questions, namely: what is the complete response (CR) rate at 3 months? This is an uncommon end point for a treatment where most CRs are only reached between month 3 and month 6 and where reports in the literature have not reported CR rates at 3 months. The major overall discrepancy of the results of this study, as compared with the literature, is the very low CR rate in both the melphalan alone group (25%) and the melphalan plus TNF group (26%), while all previous reports from Europe as well as the United States show that melphalan alone produces on average a 50% CR rate in patients with in-transit melanoma metastases and melphalan plus TNF produces a CR rate of 70%. Nine reports on sizable series of patients treated with melphalan plus TNF ( 20 to 100 patients) reported CR rates of 59% to 90%.¹ The authors discussed their results in view of previous experience of the American College of Surgeons Oncology Group² and the several European trials that suggested a higher efficacy of ILP with melphalan plus TNF with or without interferon gamma.^3-5 It must be stressed that all these trials reported very similar results in contrast with this study. Moreover, we would like to point out that CR rate at 6 months was 42% for TNF plus melphalan versus 20% for melphalan alone in the present study,¹ but that a significant number of patients are lost for evaluation, which makes the results of this trial very hard to interpret. The authors stressed the fact that several differences could explain the negative results of this study. We agree that patient selection is a very critical issue and at the same time are surprised at how little information is provided on the patient characteristics, since tumor stage (IIIA: in-transit metastases only; IIIB: in-transit metastases + regional nodal metastases; IV: in-transit metastases + distant metastases) was shown to correlate highly with response rates in the 100 ILP Rotterdam series (CR rates, 82%, 63%, and 43%, respectively).⁴ Moreover, the article does not describe whether patients were stratified for bulky disease, nor does it mention the criteria despite the fact that their previous randomized controlled trial in the United States had indicated that bulky in-transit metastases respond far better (P < .05) to the combination of TNF with melphalan.² We want to emphasize here that the 60% CR rate in the United States study in bulky disease is identical to the 59% CR rate for bulky disease in the Rotterdam report.⁴ ILP with melphalan alone performs poorly in bulky melanoma (CR rate of 13%²) whereas the combination with TNF yields a 60% CR rate.^2,4,6 This paradoxical effect is ascribed to the improved tumor penetration of melphalan in presence of TNF⁷ and the fragile angiogenic network of big tumors as compared with small in-transit metastases. This is exactly the reason why ILP with chemotherapy alone in locally advanced soft tissue sarcoma has uniformly failed,⁸ whereas ILP with TNF plus melphalan has been highly successful in multicenter pivotal trials, as well as multiple single center reports, after the European Agency for the Evaluation of Medical Products in Europe approved TNF for this indication.^5,9 Indeed, apart from the immediately enhanced drug (melphalan) uptake in the tumor mediated by TNF, the other mechanism whereby TNF works is an effect that comes 24 hours after ILP—it induces apoptosis of endothelial cells in angiogenic vessels.^10,11 In other words, there should be no tumor histologic type restriction to the effect of TNF as it mainly acts on the tumor angiogenic endothelial cells. They are normal host cells and should not differ much from one tumor type to the other. For example, the efficacy of ILP with TNF and melphalan was reported in soft tissue sarcomas, non-melanoma skin tumors, and osteosarcoma.⁸ The current attitude in Europe is to consider that bulky melanoma is a condition similar to soft tissue sarcomas, and to offer off-label ILP with TNF plus melphalan to such patients, as well as for any limb threatening tumor, regardless of histotype.⁸ In Switzerland, the authorities have recently registered ILP with melphalan plus TNF for advanced melanoma of the limbs. Lastly, it should be noted that grade 3 to 4 toxicities do not address hepatic and renal toxicity, nor neurapraxia. Despite this, the percentages of toxicities reported are significantly higher than what has been reported in other big series and undercuts the conclusion that the combination with TNF would be more toxic than ILP with melphalan alone.^5-9

In summary, we find the time point of the primary end point of this trial unusual and confusing, we find the trial report very lacunary on patient and tumor characteristics, and consider the conclusion that TNF is ineffective in this setting quite debatable since CR rate at 6 months was twice as high for TNF and that the true indication (ie, bulky disease) was not analyzable from this report. We want to stress that the major indication for the role of TNF in the management of locally advanced melanoma is bulky disease.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Ferdy J. Lejeune, Boehringer Ingelheim, Ingelheim, Germany; Alexander M.M. Eggermont, Boehringer Ingelheim GmBh Stock: N/A Honoraria: N/A Research Funds: Ferdy J. Lejeune, Boehringer Ingelheim, Ingelheim, Germany Testimony: N/A Other: N/A

REFERENCES

1. Cornett WR, McCall LM, Petersen RP, et al: Randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone compared with melphalan plus tumor necrosis factor: American College of Surgeons Oncology Group Trial Z0020. J Clin Oncol 24:4196-4201, 2006[Abstract/Free Full Text]

2. Fraker DL, Alexander H, Ross MI, et al: A phase III trial of isolated limb perfusion for extremity melanoma comparing melphalan alone versus melphalan plus tumor necrosis factor (TNFa) plus interferon-gamma(IFN). Ann Surg Oncol 9:S8, 2002 (abstr 1)[CrossRef]

3. Lienard D, Eggermont AM, Koops HS, et al: Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: A multicentre randomized phase II study. Melanoma Res 9:491-502, 1999[Medline]

4. Lejeune FJ, Kroon BB, Di Filippo F, et al: Isolated limb perfusion: The European experience. Surg Oncol Clin N Am 10:821-832, 2001[Medline]

5. Grünhagen DJ, Brunstein F, Graveland WJ, et al: One hundred consecutive isolated limb perfusions with TNF-alpha and melphalan in melanoma patients with multiple in-transit metastases. Ann Surg 240:939-947, 2004; discussion 240:947-948, 2004[CrossRef][Medline]

6. Rossi CR, Foletto M, Mocellin S, et al: Hyperthermic isolated limb perfusion with low dose tumor necrosis factor-alpha and melphalan for bulky in transit melanoma metastases. Ann Surg Oncol 11:173-177, 2004[Abstract/Free Full Text]

7. de Wilt JH, ten Hagen TL, de Boeck G, et al: Tumour necrosis factor alpha increases melphalan concentration in tumour tissue after isolated limb perfusion. Br J Cancer 82:1000-1003, 2000[CrossRef][Medline]

8. Grünhagen DJ, de Wilt JHW, ten Hagen TLM, et al: Technology insight: Utility of TNF-alpha-based isolated limb perfusion to avoid amputation of irresectable tumors of the extremities. Nature Clin Pract Oncol 3:94-103, 2006[CrossRef]

9. Eggermont AMM, Schrafford Koops H, Klausner JM, et al: 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. Ann Surg 224:756-764, 1996; discussion 224:764-765, 1996[CrossRef][Medline]

10. Ruegg C, Yilmaz A, Bieler G, et al: Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma. Nat Med 4:408-414, 1998[CrossRef][Medline]

11. van Horssen R, ten Hagen TLM, Eggermont AMM: TNF-alpha in cancer treatment: Molecular insights, antitumor effects, and clinical utility. Oncologist 11:397-408, 2006[Abstract/Free Full Text]

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