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EDITORIALS |
From the Department of Surgical Oncology (JHWdeW), Erasmus MC, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; and Sydney Melanoma Unit (JFT), Sydney Cancer Centre, Royal Prince Alfred Hospital and Department of Surgery, University of Sydney, Sydney, NSW, Australia.
Correspondence: Address correspondence to: John F. Thompson, MD, The Sydney Melanoma Unit, Royal Prince Alfred Hospital, Missenden Rd., Camperdown NSW 2050, Australia; Fax: 61-2-9550-6316; E-mail: thompson{at}smu.org.au
In this issue of the Annals of Surgical Oncology, Rossi et al.1 report the successful treatment of patients with bulky in transit melanoma metastases by isolated limb perfusion (ILP) using low-dose tumor necrosis factor alpha (TNF
) and melphalan (L-PAM). Their report is of particular interest because limited therapeutic options are currently available for such patients. Since it was first introduced in the 1950s,2 ILP with melphalan has been the standard therapy offered in this situation at many melanoma treatment centers around the world.3,4 In 1992, however, Lienard et al.5 reported ILP using TNF and interferon gamma (IFN
) in combination with melphalan for patients with melanoma and sarcoma, and demonstrated impressive antitumor effects. It was soon apparent that bulky soft tissue sarcomas, previously demonstrated to respond poorly to ILP with standard cytostatic agents,6 responded well to ILP using TNF with melphalan. A multicenter trial in Europe found that TNF-based ILP (with or without IFN) produced an overall response (OR) rate of 76% and a limb salvage rate of 71%.7 On the basis of these results, approval was given by the European Medicine Evaluation Agency (EMEA) for the use of TNF to treat locally advanced, high-grade soft tissue extremity sarcomas.
In patients with melanoma, the role of TNF, administered with melphalan by ILP, is less clear-cut. Indeed, the role of ILP itself in the treatment of patients with recurrent or intransit melanoma, although important, is limited, as we have previously suggested.8 In most cases other treatment modalities are more appropriate, depending on the number and size of the tumor deposits. As well as simple surgical excision, cryotherapy, diathermy fulguration, laser treatment, radiofrequency ablation, and direct injection of cytotoxic agents are all effective options for patients with a limited number of small lesions.9 For those with a larger number of small lesions, various investigational vaccination protocols are being tested, with occasional long-term responses.10
For the remaining small group of melanoma patients with bulky recurrent disease or multiple large in-transit metastases, not easily treated by simple local therapies, regional chemotherapy with vascular isolation is generally accepted as the treatment of choice, and sometimes provides the only alternative to amputation. With systemic chemotherapy using dacarbazine, the standard first-line drug for patients with metastatic melanoma, only a 15% to 20% partial response (PR) rate can be expected, and a complete response (CR) is rarely observed. ILP is the most commonly used regional chemotherapy modality, but an isolated limb infusion (ILI) technique developed at the Sydney Melanoma Unit is simpler, less invasive, and less expensive than ILP, yet it produces similar results.11,12 Numerous single center and multicenter ILP studies have been reported in the literature.4 The median complete response rate for all reported ILP studies with melphalan is approximately 50%, and the OR rate approximately 85%. Addition of high dose TNF (3 to 4 mg) seems to improve the CR rate after ILP to approximately 75% and the OR rate to approximately 95%.
The use of TNF, administered by ILP, raises several concerns. The first is the possibility of serious systemic toxicity if significant systemic leakage of TNF occurs. The second is the considerable expense of the agent. Third is the lack of clinical trial evidence that response rates using TNF and melphalan are actually greater than those achieved using melphalan alone. The protocol for ILP with low-dose TNF and melphalan reported by Rossi et al.1 greatly diminishes the first two of these concerns. Twenty patients with bulky melanoma metastases on limbs were treated with a fourfold lower dose of TNF than the EMEA-approved dose for patients with sarcoma. Using a lower dose of TNF without compromising response rates should have a major effect on reducing cost and, whereas several reports of ILP with melphalan and high dose TNF have demonstrated that the procedure is generally safe, even in elderly patients,13 lowering the TNF dose should further reduce the risk of systemic toxicity due to TNF leakage.
The remaining important question is whether TNF is really necessary in ILP for recurrent and in-transit melanoma metastases. In the small group of patients treated by Rossi et al.,1 CR and OR rates were high (70% and 95%, respectively), suggesting that a lower TNF dose might be as effective as a higher dose. This observation is in line with clinical results observed in a previous small series of patients with melanoma14 and experimental results in a rat sarcoma ILP model.15 In the latter study a fivefold reduction of the TNF dose correlating to the high dose regimen used clinically did not lead to reduced antitumor effects. Further reduction of the TNF dose, however, was associated with a complete loss of the synergistic antitumor effects of TNF and melphalan. In a randomized, multicenter phase III trial in five US hospitals, OR rates were not significantly different for a group of 51 patients with melanoma treated with melphalan alone (96%) compared with a group of 52 patients treated with the combination of TNF, IFN, and melphalan (81%).16 In a subgroup of patients with high tumor burden (i.e., more than 10 lesions or lesions larger than 5 cm), however, the CR rate was 58% in the group of patients treated with the combination of melphalan, TNF, and IFN. This was significantly higher than the 19% CR rate in the group of patients treated with melphalan alone.
In the study by Rossi et al., only 4 of the 20 patients had tumors that exceeded 1 cm in size; all other patients had multiple metastases (>15), but they were small in size. A large phase III study of prophylactic ILP with melphalan in patients with primary limb melanomas showed that this form of therapy was not effective in eliminating microscopic disease.17 Tumors that are large enough to have developed their own blood supply, however, usually have good uptake of cytostatics and respond well after ILP or ILI with melphalan alone, both in clinical studies18 and in various experimental tumor models.19 In our own centers, we have noted that the number of lesions does not seem to be an important predictor of response (unpublished data). It is unclear, therefore, whether the addition of TNF was important in most of the patients treated in the study of Rossi et al.1 Very large tumors, however, tend to be inhomogeneous and have poor overall drug uptake in contrast to smaller tumors. As a consequence, their treatment is improved by the immediate TNF-mediated effects such as vasodilatation, redistribution of blood flow, and increased capillary leakage, all of which result in an enhanced tumor uptake of melphalan, as was demonstrated in experimental tumor models.20 The later TNF-mediated effects, in particular selective destruction of the tumor vasculature,21 further enhance the response in larger tumors. Thus, patients with large melanoma metastases are most likely to benefit from the addition of TNF during ILP.3,22
The term bulky metastases, therefore, should be defined carefully and a distinction drawn between multiple small lesions and large, sarcoma-like metastases. For multiple small melanoma metastases, ILP or ILI using melphalan alone is probably the treatment modality of choice, producing high overall response rates. The addition of TNF has a limited effect on such tumors. Patients whose disease recurs or who fail to respond after ILP or ILI with melphalan alone,23 and patients with large, sarcoma-like lesions with a well-developed tumor vasculature are candidates for an ILP using both melphalan and TNF. The study reported by Rossi et al.1 suggests that low dose TNF (1 mg) is as effective as the higher dose schedule (4 mg) used previously. Further randomized studies are required, however, to establish that the use of TNF in patients with melanoma produces results that are significantly better than those achieved by ILP with melphalan alone.
Received for publication December 9, 2003. Accepted for publication December 16, 2003.
REFERENCES
and melphalan for bulky in-transit melanoma metastases. Ann Surg Oncol 2004; 11: 173–7.
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