] The purpose of this review is to provide
information about the place, dose and technique of curative
radiotherapy in this disease, which is a serious
cause of mortality in AIDS patients.
TREATMENT APPROACHES IN KAPOSI
SARCOMA
Kaposi sarcoma is a highly heterogeneous disease, and
many different treatment options are available. Therapies
can vary significantly depending on the clinical
type, stage, and immune system status of the disease.
Distinguishing between limited cutaneous disease
and advanced disease is an important step in selecting
the treatment modality. While there is no definitively
agreed-upon definition, limited cutaneous disease is
considered to be present when there are up to five lesions
or <5% of the body surface area.[] Optimizing
the immune system is a critical step in the treatment
process in all clinical types and stages of the disease.
[,,] If possible, medications that may cause iatrogenic
immunosuppression should be discontinued. People
living with human immunodeficiency virus (HIV)
benefit from appropriate ART.[,] One of the most
significant side effects of ART is immune reconstitution inflammatory syndrome (IRIS), which can occur 3-6
months after starting treatment. IRIS is characterized
by a paradoxical worsening of Kaposi's symptoms after
starting ART. Patients taking glucocorticoids or those
with severe immunodeficiency are at higher risk for
IRIS.[,] The development of IRIS is an indication
for the immediate initiation of systemic therapy. Topical
treatments are a treatment option for limited cutaneous
disease. Alitretinoin gel is the most commonly used
topical treatment agent.[] Imiquimod, an immunomodulator,
is another topical treatment option with
its antiviral activity.[] Intralesional chemotherapy is
a proven treatment option for limited mucocutaneous
disease. The chemotherapeutic agent of choice is vinblastine
or vincristine.[,] Cryotherapy is one of the
treatment options for limited cutaneous disease. Cryotherapy
is based on the principle of inducing necrosis
by freezing cells. Liquid nitrogen is generally used for
cryotherapy. Studies have shown that cryotherapy is a
safe and effective treatment option for limited cutaneous
disease.[] Local excision is one of the treatment
options that can be applied in limited cutaneous disease.[] Literature data on local excision in Kaposi sarcoma
has been described specifically for HIV-negative
patients. Systemic treatment is also one of the treatment
modalities that has proven its effectiveness in the disease.[] Liposomal doxorubicin is the first-line agent
for systemic therapy. Liposomal doxorubicin increases
the risk of neutropenia. Another systemic treatment
option is paclitaxel.[] According to the randomized
study, although there was no significant difference in
efficacy between liposomal doxorubicin and paclitaxel,
there was a difference in terms of side effect profile.[]
Kaposi sarcoma is considered a radiosensitive tumor.
Radiotherapy is one of the treatment options for both
limited cutaneous and advanced disease.
To briefly summarize treatment options based on
disease stage: Asymptomatic HIV-positive patients with
limited cutaneous involvement may receive ART alone.
Symptomatic patients with limited cutaneous involvement
may receive ART, radiotherapy, topical therapy,
intralesional chemotherapy, cryotherapy, or local excision.
For advanced cutaneous, oral, visceral, or nodal
disease, the recommended treatment is ART combined
with systemic therapy. Patients not suitable for systemic
therapy may receive ART combined with radiotherapy.
Radiotherapy in Kaposi Sarcoma
When examining studies on radiotherapy in Kaposi
sarcoma, the lack of prospective studies is striking. A
retrospective study by Cooper et al.[] evaluated 226 lesions treated with radiotherapy. While the dose was
30 Gy/10 fractions in most patients, an 8 Gy/1 fraction
regimen was preferred in patients with large tumors. At
the 1-month post-treatment evaluation, the complete
response rate was 68%. Local recurrence was detected
in 9% of patients. The treatment objective, anatomic
location, and patient performance score were found to
be predictive factors for treatment response. It was emphasized
that patient selection should be considered a
factor affecting radiotherapy response. In a retrospective
study conducted by Piedbois et al.[] on 453 patients,
patients were divided into two groups based on
anatomic location. In the study, 4 MeV electron beam
energy, 45-100 kV and 4 MV X-ray were used. Patients
who received treatment for the conjunctiva, eyelid, lips,
hands-feet, penis, oral mucosa and anal region were
evaluated in the first group and a dose of 10-20 Gy was
applied to this group (2.5 Gy/fraction; 4 fractions per
week). Patients who received treatment for other skin
parts were evaluated in the second group and a dose of
30 Gy was applied to this group (20 Gy in the first two
weeks, 10 Gy after a 2-week break). In the first group,
the overall rate of objective response was found to be
87.8%. Although tolerance to treatment was found to
be good, the rate of mucosal side effects was found to be
high in the oropharyngeal region. In the second group,
the complete regression rate was found to be 85% and
tolerance to treatment was found to be acceptable. 15.2
Gy was given to oral region lesions; 20 Gy was given to
conjunctiva, eyelid, lips, hands-feet, penis and anal region
lesions; In other cutaneous lesions, a dose of 30 Gy
has been reported to provide high response rates with
an acceptable toxicity profile. It has been stated that
prophylactic antifungal therapy should be considered
in the treatment of oropharyngeal lesions. In Kirova's
retrospective study of 643 patients, a total of 6,777 sites
were irradiated.[] The study used 4 MeV electron
beam energy, 4 MV, and 45-70 kV X-rays. Doses ranging
from 10 to 30 Gy were applied. The objective response
rate (complete + partial response) was found to
be 92%. While the treatment was found to be tolerable
for cutaneous lesions, mucosal reactions in oral lesions
were observed to begin at relatively low doses. 15 Gy for
oral lesions, 20 Gy for eyelid, conjunctival, and genital
lesions, and 30 Gy for skin lesions were found to be effective
treatment response rates. A retrospective analysis
evaluated 1,482 lesions treated with radiotherapy.
[] Seven hundred eleven lesions were classic Kaposi
sarcoma and 771 were HIV-associated Kaposi sarcoma.
Doses ranging from 10 to 40 Gy (mean 29.2 Gy) were
applied to the classic type, and doses ranging from 5 to 45 Gy were applied to the HIV-associated type. Based
on a 13.5-year post-treatment analysis, the cure rate for
the classic type was 98.7%. When cosmetic results were
evaluated in the classic type patients with complete response,
75.6% had good cosmetic results, and 24.39%
had acceptable cosmetic results. At 4 years of follow-up
after the end of treatment, the complete response rate in
the HIV-associated group was 91.43%. When cosmetic
response was evaluated in the HIV-associated group
with complete response, 20% of patients had good cosmetic
responses and 80% had acceptable cosmetic responses.
Of the 564 patients with acceptable cosmetic
responses, 560 experienced hyperpigmentation, and 4
experienced hypopigmentation. The study concluded
that radiotherapy is a safe and effective treatment modality
for Kaposi sarcoma. A retrospective study of 17
patients from Taiwan evaluated the results of radiotherapy
administered to patients diagnosed with classic
Kaposi sarcoma.[] All lesions treated with radiotherapy
were in the lower extremities. The most commonly
used radiotherapy regimen is 39 Gy/3 fractions. The
complete response rate was found to be 76%. 5-year
progression-free survival was 58%, and overall survival
was 85%. An Italian study evaluated the results of radiotherapy
applied to 38 lesions in 18 patients.[] A total
of 24-30 Gy was administered daily at 2 Gy with 6-18
MeV electron energy to 8 patients with multiple lesions
on the arms and legs. One of these patients also had a lesion
on the eyelid, which was administered a daily dose
of 2 Gy and 30 Gy. Seven patients with single lesions on
the arms and legs received daily doses of 20-36 Gy with
6 MV photon energy. Two patients received oral mucosal
lesions at 2 Gy and 24-30 Gy. One patient received a
daily dose of 3 Gy and 30 Gy to a single bone lesion in
the spinal column. Complete response was observed in
83.8% of the lesions, and partial response in the remaining.
The mean follow-up period was 51 months, and no
recurrence of any lesion was observed during followup.
The mean overall survival was 57.4 months. 65.7%
of the patients achieved a good cosmetic response. No
side effects requiring treatment discontinuation were
observed. An effective palliative response was achieved
except for lesions in the vertebrae and hard palate. The
study concluded that radiotherapy is an effective treatment
modality that can be the primary treatment modality
in patients with cosmetic preservation concerns.
With a complete response rate of 60-93% and a highly
tolerable side effect profile, radiotherapy stands out as a
treatment modality of choice for all stages and anatomic
locations of Kaposi sarcoma. Studies on radiotherapy in
Kaposi sarcoma and their results are shown in Table 1.
Table 1 Studies on radiotherapy in Kaposi sarcoma and their results
Table 1 Cont.
Radiotherapy Techniques, Dose/
Fraction Regimes in Kaposi Sarcoma
Electrons, kV photons and MV photons
were used in the radiotherapy of Kaposi
sarcoma, a disease that is very sensitive
to radiotherapy.[-] Three-dimensional
radiotherapy, intensity-modulated
radiotherapy (IMRT), or volumetric
arc therapy (VMAT) may be preferred
as a planning technique. Park et al.[]
compared photon beam, electron
beam, high dose rate (HDR) brachytherapy,
VMAT, and IMRT techniques
in patients with foot skin lesions. The
study concluded that VMAT provides
a dosimetric advantage in multitarget
planes. Nicolini et al.[] compared
VMAT with electron beam techniques
in patients with lower extremity lesions.
The study concluded that VMAT provides
greater bone protection than electron
therapy, but also requires a shorter
treatment time. One study published
the early results of a second series of
VMAT radiotherapy administered to a
patient who had a relapse approximately
1.5 years after receiving radiotherapy
for lesions in the right lower extremity.
[] The patient received 20 Gy/5 fractions
in the first treatment and received
33 Gy/11 fractions in the second series
of treatments. At the 4-week posttreatment
follow-up, the lesion was observed
to have completely resolved. The
patient was noted to have mild edema
and tenderness in the lower extremities.
In patients undergoing external
beam radiotherapy for Kaposi sarcoma,
the appropriate energy and treatment
technique should be selected based on
the depth and extent of the lesion.[]
Brachytherapy is one of the radiotherapy
modalities of choice for Kaposi
sarcoma. Studies have used HDR
as the brachytherapy technique. In
one study, high-dose Microselectron
brachytherapy was administered to six
patients with palatal Kaposi sarcoma.
[] A dose of 24 Gy/3 fractions was
administered. Complete response was observed in all lesions, with no side effects other than
mild-to-moderate mucositis and no recurrence in the
treated areas. Kasper et al.[] evaluated the results of
HDR with Ir-192 in 16 patients. Patients received doses
of 24-35 Gy in 4-6 fractions. Complete responses were
observed in all patients, and no local recurrence was
observed in this study, with a median follow-up of 41
months. Side effect rates were found to be quite tolerable,
with only one patient experiencing late skin side effects
(telangiectasis, hypopigmentation). Ruiz et al.[]
evaluated the results of brachytherapy applied to five
lesions with a Valencia applicator. All treated lesions
were in the lower extremities, and a dose of 25 Gy/5
fractions was administered. Median follow-up was 15
months, and all lesions showed a complete response,
and no local recurrence was observed in any patient.
A noteworthy finding was the observation of grade 2
erythema in only one lesion. Studies indicate that HDR
brachytherapy is a highly effective and safe treatment
option for Kaposi sarcoma in appropriate patients. The
appropriate dose-fractionation regimen for patients
undergoing brachytherapy is unclear. Numerous different
dose-fractionation regimens have been used in
studies. A logical approach is to base decisions on the
location, size, and clinical circumstances of the lesion.
In Kaposi sarcoma radiotherapy, numerous dosefractionation
regimens have been tested in the literature.
[-] In the studies of Piedbois and Kirova, different
doses were defined for lesions in different anatomical localizations.[,] In a prospective study of 57 patients
conducted by Harrison et al.,[] 16 Gy/4 fractions was
compared with 8 Gy/1 fr. The study found no significant
difference in response rates or skin pigmentation
between the two regimens. The 8 Gy/1 fraction regimen
was found to be an effective treatment for patients with
limited life expectancy. In Geara's retrospective study of
149 patients, the 20 Gy/8 fraction regimen was found to
have a lower response rate than the 30 Gy/12 fraction
regimen.[] In a study conducted by Saran et al.[38]
on 43 patients, doses above 20 Gy administered with
a conventional fractionation regimen were found to be
significantly superior in terms of response rate compared
to doses below 20 Gy. In a randomized controlled
study conducted by Stelzer et al.,[] 8 Gy/1 fraction, 40
Gy/20 fractions and 20 Gy/10 fraction regimens were
compared. The complete response rate was significantly
higher in the 40 and 20 Gy regimens compared to 8
Gy. The recurrence rate at the lesion site was found to
be lower in the 40 Gy regimen compared to the other
regimens. The loss of residual purple pigmentation was
also found to be higher in the 40 Gy regimen compared to the other regimens. The study's results indicate that
the response rate increases with higher doses of fractionated
radiotherapy. In a retrospective study by Oysul
et al.,[] it was found that normalized total dose 2
Gy ≥ 20 Gy doses had a higher complete response rate
than doses <20 Gy. In a randomized study by Singh, 24
Gy/12 fractions were compared with 20 Gy/5 fractions
in 60 patients.[] The study found no significant differences
between the groups in terms of response rate,
local control, acute toxicity, or late toxicity. Based on the
literature review, it is not possible to establish a clear
dose-fractionation regimen for Kaposi sarcoma radiotherapy.
Numerous dose-fractionation regimens are
available, depending on the patient's general condition,
the number of lesions, and their location.[-] Multidisciplinary
guidelines recommend doses of 30-36
Gy/2-3 Gy/fraction.[] The NCCN guidelines also
state that regimens of 6-8 Gy/1 fraction, 20 Gy/5 fractions,
24 Gy/12 fractions, 30 Gy/10-15 fractions, and
40 Gy/20 fractions can be used.[] The rates and severity
of side effects associated with radiotherapy can
vary depending on the area being treated. Side effects
may be more common and more severe in oral treatments
than in skin lesions.[,] Radiotherapy-related
side effects can be said to be mild and treatment tolerance
is high.[,] The most common skin side effect
is grade 1 radiodermatitis.
