Phase II trial of intralesional therapy with interleukin-2 in soft-tissue melanoma metastases

Abstract

The objective of the present study was to validate the use of intralesional injection of interleukin-2 (IL-2) in patients with skin and soft-tissue melanoma metastases. A total of 24 patients with AJCC stage III or IV melanoma and single or multiple skin and soft-tissue metastases were included. Interleukin-2 injections were administered intralesionally into the total number of cutaneous and soft-tissue metastases accessible from the skin, 2-3 times weekly, over 1-57 weeks. Single doses varied from 0.6 to 6 x 10(6) IU, depending on lesion size. The clinical response was monitored by sonography and confirmed by histopathology; response evaluation was confined to the intralesionally treated tumours. Complete response (CR) of the treated metastases was achieved in 15 patients (62.5%), the longest remission lasting 38 months to date. In five patients, partial response (PR) was achieved (21%) and in another three patients, progressive disease was observed (one patient not assessable). A total of 245 metastases were treated with CR in 209 (85%), and PR in 21 (6%). The therapy was generally well tolerated; the observed adverse events were mainly of grade 1-2 severity. Immunohistochemical studies showed the tumour cells undergoing apoptosis and revealed a mixed character of the inflammatory infiltrate. The unusual high CR rate in metastatic melanoma of 62.5% and the limited toxicity suggest that treatment of skin and soft-tissue melanoma metastases with intralesional injection of IL-2 may be a safe and effective alternative to conventional therapies. The optimal dosage and duration of this therapy still remain to be defined in larger prospective multicentre trials.

Figure 1

Histology of biopsies taken after the completion of therapy. Complete necrosis of the tumour tissue and a mainly peritumoral lymphocytic infiltrate (A) haematoxylin and eosin; original magnification × 40. No viable tumour cells are recognisable; necrotic tumour cells appear as cell shadows. Furthermore, monocytes and macrophages are seen. (B) Haematoxylin and eosin; original magnification × 200.

Figure 2

Immunoflourescence staining for Melan A/Mart-1 (green) and caspase-3 (red) detects vital and apoptotic tumour cells. Nuclei stained blue. Images were taken using a CLSM at 630-fold magnification (A). Confocal laser scanning microscopy image of the inflammatory infiltrate: CD3-positive T-lymphocytes stained blue, CD56-positive/CD3-negative NK cells stained red, nuclei green, final magnification 630-fold (B). Most NK cells are found in small groups near to a capillary (arrow).

Figure 3

Survival of patients treated with intralesional administered IL-2. Time of diagnosis of stage III respective stage IV disease was taken as the start point for survival curves.

Figure 4

Patient no. 2 in Table 4 with multiple melanoma metastasis at the right leg after two courses of limb perfusion and chemotherapy with vindesine before therapy (A) and after 57 weeks treatment, in which each metastasis was individually injected (B). In some lesions the response was assessed by histopathology; only residual pigment deposits in the dermis are visible. The patient is under CR to date, currently stable without treatment since 18 months.