Intralesional Treatment of Recurrent Cutaneous Melanoma Metastases
Christoph Hoeller, Astrid Cicha, Romina Nemecek, Andreas Stepan
Department of Dermatology, Medical University of Vienna, Austria
A 79-year old male patient with a history of melanoma of more than 5mm of tumour thickness on his left lower leg was referred to our centre. He underwent wide local excision 2 years prior but refused sentinel node biopsy as well as adjuvant treatment. Beginning 3 months after excision of the primary tumour he had several recurring satellite and in-transit metastases on the lower leg which were repeatedly excised. A B-raf V600E mutation was found to be present in his tumour. Due to recurrence in multiple sites he was started on a combination of a B-raf and a MEK Inhibitor. While he did have a clear clinical response of his cutaneous metastases, the patient experienced significant side effects including joint pain, muscle soreness as well as dizziness and fatigue. As these side effects did not improve with dose reduction the MEK inhibitor had to be stopped after 3 months and the B-raf inhibitor after 5 months of therapy. Subsequently regrowth of the cutaneous lesions occurred and the patient was referred to our centre.
Initial presentation and therapy:
The patients ECOG performance status was 0. Besides ongoing mild muscle soreness and joint pain he suffered from mild arterial hypertension, reflux disease, chronic venous insufficiency and struma nodosa without any changes in his thyroid function.
On his left leg a group of superficial cutaneous melanoma metastases of up to 2cm in diameter were grouped around the skin graft from the primary tumour excision (Fig. 1) A recent CT-scan did not show any sign of distant metastatic disease. His laboratory parameters were unremarkable.
The therapeutic options discussed included surgery, off label use of imiquimod or intralesional Il-2, therapy with a PD-1 inhibitor or intralesional therapy with talimogene laherparepvec (TVEC), a GM-CSF expressing herpes simplex type 1 virus, that was recently approved as an oncolytic immunotherapy for patients with injectable cutaneous and soft-tissue melanoma-metastases. Being a strictly localized disease a recommendation for the use of TVEC was made based on the availability of data from a randomised trial (ref 1, 2). The decision was discussed with the patient who gave his consent. This was the first patient treated with TVEC outside of a clinical study in Europe.
TVEC was applied intralesionally (Fig.2) in all but 1 lesion (Fig.1, yellow arrow), which was left untreated as an indicator for a systemic immune-response. An initial response was seen as early as cycle 3, at cycle 8 only flat hyperpigmented maculae were present, including the uninjected lesion (Fig. 3, 4). A biopsy confirmed the absence of viable tumour cells with the presence of melanophages and a dense inflammatory infiltrate (Fig 5). Side effects included pain at the injection site, worsening of his muscle and joint pain, which was controlled with standard doses of ibuprofen as well as chills, without fever, following injection cycles 1-3.
Continued clinical follow up has not shown any sign of local or systemic recurrence after the first 3 months.
TVEC is an effective drug for the treatment of patients with localized, injectable metastatic melanoma.
- Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA1, Spitler LE1, Puzanov I1, Agarwala SS1, Milhem M1, Cranmer L1, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780-8.
- Harrington KJ, Andtbacka RH, Collichio F, Downey G, Chen L, Szabo Z, Kaufman HL. Efficacy and safety of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in patients with stage IIIB/C and IVM1a melanoma: subanalysis of the Phase III OPTiM trial. Onco Targets Ther. 2016 Nov 16;9:7081-7093.
Fig 1: local situation before therapy. The arrow indicates the uninjected lesion
Fig 2: Intralesional application of TVEC at cycle 1. A fluid impermeable dressing is applied for 1 week following the injection of TVEC.
Fig. 3: Clinical response to TVEC.
Fig.4: Response was observed in injected as well as in an uninjected lesion (arrow)
Figure 5: Histopathology showed melanophages and a dense, superficial and deep inflammatory infiltrate.