Isolated limb perfusion with melphalan for melanoma

Nieweg, Omgo E.; Kroon, Bin B. R.

doi:10.1002/jso.23558

Cited by 37 publications

(29 citation statements)

References 64 publications

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“…To this end, we studied the effects of melphalan (Mel), the regionally applied (standard-of-care) chemotherapeutic for extremities-associated melanoma (20,22). Melphalan is an alkylating agent, used in the isolated limb perfusion (ILP)/infusion (ILI) therapy (20,22), for patients harboring limb-localized malignancies (23).…”

Section: Introductionmentioning

confidence: 99%

“…Melphalan is an alkylating agent, used in the isolated limb perfusion (ILP)/infusion (ILI) therapy (20,22), for patients harboring limb-localized malignancies (23). Melphalan-based ILP/ILI (Mel-ILP/Mel-ILI) is considerably effective, with a significant fraction of patients (25%-53%) displaying complete clinical responses and various others showing partial responses (14%-39%; ref.…”

Section: Introductionmentioning

confidence: 99%

“…Melphalan-based ILP/ILI (Mel-ILP/Mel-ILI) is considerably effective, with a significant fraction of patients (25%-53%) displaying complete clinical responses and various others showing partial responses (14%-39%; ref. 22; clinical metadata analysis; Supplementary Table S1). Hitherto, melanoma cell-killing efficacy is postulated as the sole contributor to patients' responsiveness toward melphalan treatment (24).…”

Section: Introductionmentioning

confidence: 99%

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Antitumor Immunity Triggered by Melphalan Is Potentiated by Melanoma Cell Surface–Associated Calreticulin

et al. 2015

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Systemic chemotherapy generally has been considered immunosuppressive, but it has become evident that certain chemotherapeutic drugs elicit immunogenic danger signals in dying cancer cells that can incite protective antitumor immunity. In this study, we investigated whether locoregionally applied therapies, such as melphalan, used in limb perfusion for melanoma (Mel-ILP) produce related immunogenic effects. In human melanoma biopsies, Mel-ILP treatment upregulated IL1B, IL8, and IL6 associated with their release in patients' locoregional sera. Although induction of apoptosis in melanoma cells by melphalan in vitro did not elicit threshold levels of endoplasmic reticulum and reactive oxygen species stress associated with danger signals, such as induction of cell-surface calreticulin, prophylactic immunization and T-cell depletion experiments showed that melphalan administration in vivo could stimulate a CD8 þ T cell-dependent protective antitumor response. Interestingly, the vaccination effect was potentiated in combination with exogenous calreticulin, but not tumor necrosis factor, a cytokine often combined with Mel-ILP. Our results illustrate how melphalan triggers inflammatory cell death that can be leveraged by immunomodulators such as the danger signal calreticulin. Cancer Res; 75(8);

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antitumor Immunity Triggered by Melphalan Is Potentiated by Melanoma Cell Surface–Associated Calreticulin

et al. 2015

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“…The drug choice of melphalan is grounded in clinical responses noted in the treatment of cutaneous melanoma by isolated limb perfusion and liver metastases of uveal melanoma by isolated hepatic perfusion [5,6,9]. Preclinical data support the therapeutic response of human melanoma lines to melphalan and have shown an enhanced response with hyperthermia [20,21].…”

Section: Discussionmentioning

confidence: 99%

“…Isolated limb perfusion of melphalan was first described as a single case report by Creech et al [5] in 1957 and is now a well-established technique for inoperable recurrent cutaneous melanoma affecting an extremity [6]. It consists of localized delivery of cytotoxic melphalan to the site of disease, without exposing vital organs to the consequences of these high doses.…”

Section: Introductionmentioning

confidence: 99%

Chemoreduction of Orbital Recurrence of Uveal Melanoma by Intra-Arterial Melphalan

et al. 2018

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Background/Aims: The treatment of orbital melanoma poses a management challenge. This case explores the delivery of high-dose melphalan to an orbital recurrence of uveal melanoma via intra-arterial delivery of melphalan to the orbit. A 62-year-old man developed recurrent orbital disease 7 months after enucleation for a large uveal melanoma. He received 6 monthly intra-arterial infusions of melphalan to the orbit, ranging in dose from 20 to 30 mg per infusion. Following the last infusion, mild temporary erythema was noted on the forehead along the distribution of the supratrochlear artery. The orbital recurrence was reduced in size by 66% in the longest dimension as measured by magnetic resonance imaging (MRI). However, 9 months following intra-arterial melphalan, tumor regrowth was detected on MRI, and additional treatment options were pursued. Conclusion: This case demonstrates that intra-arterial melphalan can result in nonsustained tumor regression of recurrent orbital uveal melanoma. It suggests that local delivery of high-dose melphalan may be helpful as a neoadjuvant treatment for uveal melanoma, and future studies will be useful to confirm the value of this approach in additional cases of recurrent and possibly in primary uveal melanoma.

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Isolated limb perfusion for in‐transit melanoma metastases: Melphalan or TNF‐melphalan perfusion?

Hoekstra

Veerman

Ginkel

2014

Journal of Surgical Oncology

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Indications for treatment of melanoma in-transit metastases (ITMs) confined to the limb with isolated limb perfusion (ILP) are not well defined. This study reports the Groningen regional therapeutic perfusion experience with melphalan (M-ILP) and TNF-melphalan (TM-ILP) for ITMs, and reviews of the melanoma TNF-melphalan ILP literature. Between 1991 and 2012, 60 patients were treated with ILP. Patients with "small" ITMs received M-ILP (10-13 mg melphalan/L limb volume) and patients with "bulky" disease TM-ILP (1-4 mg TNF); 19 M-ILPs and 41 TM-ILPs were performed, 26 Stage IIIB, 31 Stage IIIB and 1 stage IV disease. Overall response after 57 ILPs was 90%; CR 27 (45%), PR 27 (45%), no response 3 (5%); after 9 M-ILPs CR 6 (32%) and 41 TM-ILPs CR 21 (51%, P = 0.124). For younger patients (<65 years) CR was 69% and for elderly patients 29% (P = 0.003). For low volume disease (<5 ITMs) CR was 75% and for high volume disease (≥5 ITMs) 41% (P = 0.038). After median follow-up of 15 months (range, 1-144) there was local recurrence or disease progression in 36 patients (60%). Positive lymph node status was associated with local progression, absence of CR and Stage IIIC disease; these were independent prognostic factors for progression to systemic disease. M-ILP is an effective regional treatment for melanoma ITMs, whereas for bulky disease TM-ILP should be the first choice. In-field progression-free survival after ILP is determined by the biological behavior of the ITMs and the patient's immune system.

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Isolated limb perfusion with melphalan for melanoma

Cited by 37 publications

References 64 publications

Antitumor Immunity Triggered by Melphalan Is Potentiated by Melanoma Cell Surface–Associated Calreticulin

Antitumor Immunity Triggered by Melphalan Is Potentiated by Melanoma Cell Surface–Associated Calreticulin

Chemoreduction of Orbital Recurrence of Uveal Melanoma by Intra-Arterial Melphalan

Isolated limb perfusion for in‐transit melanoma metastases: Melphalan or TNF‐melphalan perfusion?

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