ARTICLE
Auteur(s) : Tomoko Inaba1, Kei-ichi
Yamanaka1,2, Kunihiko Asahi1, Youichi
Omoto1, Kenichi Isoda1, Daniel
Hurwitz2, Thomas S Kupper2, Hitoshi
Mizutani1
1Department of Dermatology, Mie University Faculty of
Medicine, Mie, Japan, Faculty of Medicine, 2-174, Edobashi, Tsu,
Mie, 514-0101, JapanFax: (+81) 1 59 231 5206.
2Harvard Skin Disease Research Center, Department of
Dermatology, Brigham and Women’s Hospital, Boston, Massachusetts,
USA
SirAs Autio et al. reported recently [1], angiosarcoma is an
aggressive tumor and resistant to treatments because of the nature
of the malignancy. At present, combination therapy with surgical
resection, radiation, chemotherapy, and immunotherapy is the
mainstay of treatment. Although this combination therapy is
initially effective, recurrence is commonly unavoidable because of
the rapid and wide spreading of the tumor cells. Angiosarcoma is
considered to have one of the worst prognoses among skin cancers
[2, 3]. Recombinant human interleukin-2 (rhIL-2) has been used for
the treatment of angiosarcoma because it has a direct effect on
tumor cells and also activates natural killer (NK) cells, and
lymphokine-activated killer (LAK) cells [4], however it has
limitations in induction of the cytotoxic cytokines, inflammatory
cytokines and interferons. Moreover, cell mediated immunity is
often compromised in patients with malignancies. To conduct
anti-tumor reactions by rhIL-2, an additional immunotherapy that
primes anti-tumor cytotoxic inflammatory reactions is required.
OK-432, a penicillin- and heat-inactivated lyophilized powder of a
Streptococcus pyogenes A3 sub strain, has been used in Japan as an
anti-tumor immunomodulatory agent for gastric cancer and primary
head and neck cancer [5, 6]. During the process of OK-432
treatment, Toll-like receptor 4 (TLR4) on dendritic cells (DCs)
recognize OK-432 polysaccharide antigen, which is an active
component of OK-432; this event initiates signaling pathways that
culminate in the expression of inflammatory genes [7, 8]. In
addition, it has been reported that OK-432 induces maturation of
DCs both in vitro and in vivo [9], and also stimulates DCs to
produce immune-stimulatory cytokines, including IL-12,
interferon-γ, and TNF-α. Via this process, OK-432 can activate NK
cells and LAK cells, as well skewing T-cell responses toward the T
helper 1 pole [10]. Here we report successful treatment of a large
angiosarcoma using OK-432, rhIL-2, and radiotherapy.A 77-year-old
woman consulted our clinic in April 1999. A purplish spot developed
on her face in 1998. It increased asymptomatically, and a dark
purple plaque with focal crusting covered more than 80% of her
scalp with purpura on the left orbital area at the first visit ((
figure 1A )). No
metastatic lesions were detected by intensive examinations.
Histologically irregularly composed vasculature with large,
dark-stained, atypical nuclei proliferated from the dermis to
subcutaneous tissue (( figures 1B and 1C )).
Because of her history of chronic heart failure, age, and the
extent of the tumor, surgical treatment or intensive chemotherapy
were not indicated. Then we chose a combination immunotherapy using
OK-432 and rhIL-2. Initially, 0.5 KE daily (1 Klinische Einheit
(KE) = 0.1mg lyophilized powder) of OK-432 were administered
intramuscularly for three days, and increased to 1KE daily for
three more days. Then we started intravenous infusion of rhIL-2,
400,000 U daily, with electron beam therapy (4MeV 2.5Gy daily).
During the first 10 days of treatment, her levels of NK and LAK
cell activity increased from 17.9% to 44.7% and from 2.0% to 2.6%,
respectively. Her skin lesions responded rapidly. After 30 days of
treatment with rhIL-2 and irradiation (a total of 12 million U of
rhIL-2 and 52.5Gy of irradiation), she developed a capillary leak
syndrome and this resulted in heart failure. She required treatment
in an intensive care unit for a week. After recovery, radiotherapy
was resumed for an additional 10 days. Skin lesions disappeared ((
figure 1D )) and
she achieved complete remission. Neither metastasis nor recurrence
has been observed during the five years since treatment.A recent
study reported the positive effect of the radiotherapy combined
with rhIL-2 immunotherapy [11], however angiosarcoma, especially a
large size like this case, is difficult to survive. Intermittent
addition of OK-432 in IL-2 therapy for angiosarcoma was reported
with an unsuccessful final result [12]. In contrast, we chose
initial consecutive administration of OK-432 for 6 days followed by
rhIL-2 for 30 days. The levels of NK cell and LAK cell activity
were up-regulated after combination therapy with OK-432 and rhIL-2.
Our patient developed a capillary leak syndrome, which is a
complication of rhIL-2 therapy. The precise mechanism of the
capillary leak syndrome has not been well described. The cytotoxic
white blood cells initiated by OK-432 expanded overproducing
inflammatory cytokines by IL-2, which might injure the capillary of
the lung with exudative changes in the alveolus. It is likely that
the neoplastic endothelial cells of the angiosarcoma were
simultaneously involved in this attack. The capillary leak syndrome
may represent a strong anti-tumor effect of this combination
therapy. Despite the risk of circulatory complications, OK-432 and
rhIL-2 combination therapy is a potent new therapy for life
threatening widely spread angiosarcoma.
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