Postoperative DAV‐IFN‐β therapy does not improve survival rates of stage II and stage III melanoma patients significantly

Matsumoto, Takaaki; Yokota, Kenji; Sawada, Masashi; Sakakibara, Ayako; Shibata, Shinichi; Yasue, Shizuka; Tomita, Yasushi; Yatsuya, Hiroshi; Akiyama, Mari

doi:10.1111/jdv.12040

Cited by 17 publications

(22 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DTIC is one of the most famous and long used antimelanoma drugs before the development of immune checkpoints inhibitors such as ipilimumab, nivolumab and pembrolizumab . In addition to DTIC, in Japan, intravenous administration of nimustine hydrochloride (ACNU) and vincristine (VCR) with subcutaneous injection of interferon‐beta (a regimen of DAV‐Feron therapy) has been used as adjuvant therapy for melanoma up to stage III, although the adjuvant effects are still under discussion. Indeed, Matsumoto et al reported that postoperative DAV‐IFNβ therapy did not significantly improve survival rates of stage II and stage III melanoma in 82 stage II and 60 stage III melanoma patients .…”

Section: Discussionmentioning

confidence: 99%

“…In addition to DTIC, in Japan, intravenous administration of nimustine hydrochloride (ACNU) and vincristine (VCR) with subcutaneous injection of interferon‐beta (a regimen of DAV‐Feron therapy) has been used as adjuvant therapy for melanoma up to stage III, although the adjuvant effects are still under discussion. Indeed, Matsumoto et al reported that postoperative DAV‐IFNβ therapy did not significantly improve survival rates of stage II and stage III melanoma in 82 stage II and 60 stage III melanoma patients . On the other hand, several case reports and research reports suggested the adjuvant efficacy of DAV‐IFNβ therapy .…”

Section: Discussionmentioning

confidence: 99%

“…In Japan, DAV therapy (DTIC in combination with nimustine hydrochloride (ACNU) and vincristine (VCR)) has been used in the adjuvant setting for advanced melanoma for the last 30 years. At the time its use started, a strict clinical trial was not necessary to use novel drugs clinically, and oncologists in Japan have historically used this DAV therapy for melanoma patients . As there have been no clinical trials, and there is no evidence for this chemotherapy regimen, this regimen is only used in Japan.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cytotoxic antimelanoma drugs suppress the activation of M2 macrophages

Fujimura

Kakizaki

Kambayashi

et al. 2017

Experimental Dermatology

View full text Add to dashboard Cite

Together with regulatory T cells (Tregs), tumor-associated macrophages (TAMs) play roles in maintaining the tumor microenvironment. Although cytotoxic antimelanoma drugs such as dacarbazine (DTIC), nimustine hydrochloride (ACNU) and vincristine (VCR) have been used for the treatment of malignant melanoma as adjuvant therapy in Japan, the detailed mechanisms of their immunomodulatory effects are not fully understood. As the majority of TAMs are alternatively activated M2 macrophages that favour tumor development, the aim of this study was to elucidate the immunomodulatory effects of these reagents on human monocyte-derived M2 macrophages. First, mRNA expressions and protein production of immune checkpoint molecules, PD-L1 and chemokines by CD163 + CD206 + M2 macrophages derived from peripheral blood mononuclear cells were investigated to determine the immunomodulatory effects of DTIC, ACNU, and VCR. DTIC and VCR significantly decreased PD-L1 mRNA expression, which was confirmed by flow cytometry. Moreover, the mRNA expression and production of CCL22 were significantly decreased by DTIC, which suggested that DTIC might suppress the recruitment of Tregs in the tumor site. Furthermore, the decreased expression of PD-L1 and production of CCL22 were validated in vivo, using the B16F10 mouse melanoma model, leading to abrogation of the suppressive function of T-cell proliferation. The present report suggests one of the possible antimelanoma mechanisms of DAV combination chemotherapy for melanoma patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cytotoxic antimelanoma drugs suppress the activation of M2 macrophages

Fujimura

Kakizaki

Kambayashi

et al. 2017

Experimental Dermatology

View full text Add to dashboard Cite

show abstract

“…Previously, adjuvant therapy with DAV was applied to the treatment of cutaneous melanomas . However, DAV‐feron therapy brought no significant improvement in either disease‐free survival rates or melanoma‐specific survival rates of patients with cutaneous melanomas . In Japan, nivolumab was approved for use in patients with unresectable or metastatic melanoma in July 2014.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effects of interferon‐beta and nivolumab in oral mucosal melanoma

Fusumae

Chiang

Okada

et al. 2017

The Journal of Dermatology

View full text Add to dashboard Cite

Mucosal melanoma is a rare aggressive cancer with a very poor prognosis. Clinical and pathological characteristics of mucosal melanoma differ from those of cutaneous melanoma and there are no established management guidelines for mucosal melanoma. Complete surgical excision is one of the most effective treatments for localized lesions, while targeted therapies and immunotherapies, such as monoclonal antibodies that target cytotoxic T-lymphocyte-associated molecule-4, and the programmed death (PD)-1/PD-ligand 1 pathway inhibitors, are treatment options for unresectable or metastatic lesions. Here, we describe the case of a patient with oral mucosal melanoma with multiple metastases. In our case, local injection of interferon (IFN)-b with dacarbazine-nimustinevincristine therapy provided antitumor effects on an invasive tumor on the upper gingiva. Nivolumab therapy produced complete remission of lymph node and bone metastases. In contrast, the remaining in situ portion of oral mucosal melanoma on the hard palate was refractory to IFN-b monotherapy and nivolumab therapy. However, after administration of nivolumab, peritumoral injection of IFN-b showed rapid therapeutic effects. Our case suggested that nivolumab upregulated the antitumor effects of IFN-b, which induced the recruitment of CD8 + T cells into the tumor microenvironment contributing to the deletion of tumor cells. Combination therapy of IFN-b and nivolumab may be a potential treatment option for patients with oral mucosal melanoma.

show abstract

“…Meanwhile, Japan has independently adopted therapies with IFN‐β and DAV Feron (dacarbazine, nimustine, vincristine and IFN‐β) for malignant melanoma after surgery in stage IIA or later patients based on results from a phase II single arm study. Nevertheless, no randomized comparative study has been performed to prove the efficacy of these therapies . Therefore, it was necessary to quickly introduce globally standardized treatment to Japan so that differences in medical environment could also be resolved.…”

Section: Introductionmentioning

confidence: 99%

Phase I study of pegylated interferon‐alpha‐2b as an adjuvant therapy in Japanese patients with malignant melanoma

Yamazaki¹,

Uhara

Wada

et al. 2016

The Journal of Dermatology

View full text Add to dashboard Cite

In the adjuvant setting for malignant melanoma, interferon (IFN)‐α‐2b and pegylated (PEG) IFN‐α‐2b were approved in several countries including the USA before these were approved in Japan. To resolve the “drug‐lag” issue, this phase I study was designed to evaluate the safety and tolerability in Japanese patients with stage II or III malignant melanoma who had undergone surgery, by treating with PEG IFN‐α‐2b. As with a previously reported phase III study, patients were to receive PEG IFN‐α‐2b 6 μg/kg per week s.c. during an 8‐week induction phase, followed by a maintenance phase at a dose of 3 μg/kg per week up to 5 years. Dose‐limiting toxicity and pharmacokinetics were assessed during the initial 8 weeks. Of the nine patients enrolled, two patients had dose‐limiting toxicities that resolved after discontinuation of treatment. The most frequently reported drug‐related adverse events (DRAE) included pyrexia, decreased neutrophil and white blood cell counts, and arthralgia. Grade 3 DRAE included decreased neutrophil count. No deaths, serious adverse events and grade 4 adverse events were reported. Distant metastasis occurred in one patient. No apparent differences in area under the concentration–time curve and maximum observed serum concentration were observed between Japanese and historical non‐Japanese pharmacokinetic data, suggesting no marked racial differences. No neutralizing antibody was detected in these patient samples. PEG IFN‐α‐2b was tolerated in Japanese patients, and eventually approved in Japan in May 2015 for adjuvant therapy in patients with stage III malignant melanoma. Because the number of patients was limited, further investigation would be crucial.

show abstract

Postoperative DAV‐IFN‐β therapy does not improve survival rates of stage II and stage III melanoma patients significantly

Cited by 17 publications

References 27 publications

Cytotoxic antimelanoma drugs suppress the activation of M2 macrophages

Cytotoxic antimelanoma drugs suppress the activation of M2 macrophages

Synergistic effects of interferon‐beta and nivolumab in oral mucosal melanoma

Phase I study of pegylated interferon‐alpha‐2b as an adjuvant therapy in Japanese patients with malignant melanoma

Contact Info

Product

Resources

About