Treatment with Taxanes of Refractory or Life-Threatening Kaposi Sarcoma Not Associated withHuman Immunodeficiency Virus Infection

Laurence Fardet, M.D.1

Pierre-Emmanuel Stoebner, M.D., Ph.D.2

Herve Bachelez, M.D., Ph.D.1

Vincent Descamps, M.D., Ph.D.3

Delphine Kerob, M.D.1

Laurent Meunier, M.D., Ph.D.2

Michel Dandurand, M.D.2

Patrice Morel, M.D.1

Celeste Lebbe, M.D., Ph.D.1

1 Department of Dermatology, Hospital Saint-Louis, Paris, France.

2 Department of Dermatology, University Hospitalsof Montpellier-Nimes, Nimes, France.

3 Department of Dermatology, Hospital Bichat-Claude Bernard, Paris, France.

Address for reprints: Laurence Fardet, M.D., De-partment of Dermatology, Hospital Saint-Louis, 1avenue Claude Vellefaux, 75010 Paris, France; Fax:(011) 33 142499590; E-mail: lfardet@club-internet.fr

Received July 26, 2005; revision received October1, 2005; accepted October 31,2005.

BACKGROUND. Kaposi sarcoma (KS) is an angioproliferative disease that may rep-

resent a difficult therapeutic challenge in disseminated stages. The efficacy of

taxanes (paclitaxel and docetaxel), as agents with antiangiogenic properties, has

been described previously in the treatment of patients with acquired immunode-

ficiency syndrome (AIDS)-associated KS but remains unknown in the treatment of

patients with refractory or life-threatening KS without human immunodeficiency

(HIV) infection.

METHODS. During the past 6 years, 12 non-HIV-infected patients with refractory KS

were treated with paclitaxel (175 mg/m2 every 3 wks) or docetaxel (60 mg/m2 every

3 wks).

RESULTS. All patients improved dramatically after chemotherapy. Partial desinfil-

tration (n � 6) or complete desinfiltration (n � 6) of all papulonodular skin lesions

was observed with marked improvement of lymphedema in 6 patients. According

to the AIDS Clinical Trials Group criteria, response was partial in 100% of patients.

A major response was obtained among patients who had visceral lesions (n � 3

patients), with rapid and complete remission of digestive or respiratory symptoms.

The mean delay to response was 2 courses. Treatment was sustained for 3 patients.

For the remaining 9 patients who received a median of 7 courses (range, 2-14

courses), the mean time to recurrence or follow-up without recurrence was 13

months. Tolerance was good except for 3 episodes of Grade 3 or 4 asymptomatic

neutropenia and 1 episode of moderate myositis.

CONCLUSIONS. The results of this study showed that taxanes are beneficial in the

treatment of patients with refractory or life-threatening Kaposi sarcoma. Cancer

2006;106:1785–9. © 2006 American Cancer Society.

KEYWORDS: AIDS Clinical Trials Group criteria, Kaposi sarcoma, taxanes.

Kaposi sarcoma (KS) is a human herpes virus 8-associated, multi-focal, angioproliferative disease. Four clinicoepidemiologic forms

are described: endemic or African KS, classic or Mediterranean KS,posttransplantation KS, and acquired immunodeficiency (AIDS)-asso-ciated KS. The treatment options for endemic and classic KS, whensystemic treatment is required, are interferon � (INF�) or nonmyleoa-blative or mildly myeloablative cytotoxic agents, such as vincristine,vinblastine, bleomycin, and etoposide. Response rates with thesetherapies have been evaluated poorly. Complete responses are un-usual, and partial response rates (estimated in very small series) rangefrom 60% to 80% with INF �.1,2 Anthracyclines also have been eval-uated poorly, and their cardiotoxicity is a limiting factor for their usein elderly patients. Taxanes (paclitaxel and docetaxel) are microtu-bule-stabilizing agents that have demonstrated effectiveness against

1785

© 2006 American Cancer SocietyDOI 10.1002/cncr.21791Published online 13 March 2006 in Wiley InterScience (www.interscience.wiley.com).

AIDS-associated KS. Few anecdotal reports of the suc-cessful treatment of non-AIDS-associated KS withthese agents are available in the medical literature.3–7

In this report, we describe 12 AIDS-free patients withKS who were treated successfully with taxanes afterthey had failed on prior cytotoxic or INF� treatments.

MATERIALS AND METHODSThis retrospective study included all patients withnonhuman immunodeficiency virus (non-HIV)-asso-ciated KS who received treatment with taxanes in 3separate dermatologic departments between 1998 and2004. Patients were treated either with paclitaxel 175mg/m2 every 3 weeks or with docetaxel 60 mg/m2

every 3 weeks. Treatment was interrupted when 1) astable response was attained for at least 2 months(some patients who attained a stable response hadprolonged therapy because of visceral lesions or se-vere, debilitating lymphedema), 2) progression of KSdespite 2 courses of taxane, or 3) severe toxicity. Theclinical evolution of KS was evaluated according to theAIDS Clinical Trials Group (ACTG) criteria.8 Side ef-fects were reported according to the Common Termi-nology Criteria for Adverse Events (version 3.0).9

RESULTSTwelve patients with non-HIV-related KS were treatedwith a taxane. All but 1 of those patients receivedtaxane treatment because of the inefficacy or toxicityof other specific therapies.

Table 1 summarizes the characteristics of the 12patients. There were 11 males and 1 female, in accor-dance with the male preponderance in KS.10 Theirmean age at KS diagnosis was 63 years (range, 36-86yrs); and, at the start of taxane therapy, the mean agewas 67 years (range, 46-89 yrs). Patients had classic KS(n � 7 patients), endemic KS (n � 4 patients), or post-transplantation KS (renal transplantation; n � 1 pa-tient). Three patients had cutaneous and symptom-atic, visceral KS (digestive KS with massive bleeding in1 patient and resting dyspnea in 2 patients). One pa-tient had locally aggressive, cutaneous KS with osse-ous, destructive lesions; and 8 patients had only skinlesions. Seven patients had been treated previouslywith INF�, which either was unsuccessful or was tol-erated poorly. Nine patients received docetaxel, and 3patients received paclitaxel. Treatment is ongoing for3 patients. For the other 9 patients, the mean numberof taxane infusions was 7 (range, 2-14 infusions). For 5patients, lenograstim was associated with taxane. Par-tial desinfiltration (n � 6 patients) or complete desin-filtration (n � 6 patients) of all papulonodular lesionswas observed with marked improvement of lymphed-ema in 6 patients (Figs. 1–3). For all patients, the final

evaluation, according to ACTG criteria, was a partialresponse. Moreover, major response was obtained invisceral lesions (at clinical and radiologic evaluation),with the complete disappearance of digestive or respi-ratory symptoms. Delay to response was short (mean,2 infusions; range, 1-4 infusions). After treatment, themean time to recurrence or the mean follow-up with-out recurrence was 13 months (range, 2-25 mos). Atthe time of the current report, 3 patients had stabledisease 8 months, 9 months, and 20 months after thelast taxane infusion; 5 responsive patients had diseaseprogression 2 months, 4 months, 14 months, 18months, and 25 months after the end of therapy (in-cluding 1 patient who had KS progression 6 monthsafter the start of low doses of corticosteroids for poly-myalgia rheumatica and regressed when steroids werereduced). One patient was lost to follow-up 17 monthsafter the last taxane infusion (KS was stable). Taxanetherapy was reintroduced for 4 patients with new dis-ease progression and was successful in 3 patients.

Toxicity was moderate. Grade 1 alopecia was ob-served frequently (n � 6 patients), and minor diges-tive side effects (Grade 1 diarrhea and mild nausea)occurred in 3 patients. One reported diffuse myalgiawith biologic myositis 2 months after the initiation oftaxanes which persisted despite taxane withdrawal.One patient developed asymptomatic, mild, serousedema (pleuritis and pericarditis) after 11 infusions.Asymptomatic Grade 1 (n � 1 patient), Grade 3 (n � 2patients), or Grade 4 (n � 1 patient) neutropenia and1 episode of Grade 1 thrombopenia occurred in 4patients. Therefore, in 3 patients, lenograstim wasadded to with each taxane treatment without recur-rence of neutropenia.

DISCUSSIONTwelve patients with non-HIV-associated KS whofailed to respond to INF� or cytotoxic chemotherapyimproved shortly after treatment with paclitaxel ordocetaxel. Major clinical responses were observed inall patients, and most patients showed good toleranceto the therapy.

Paclitaxel and docetaxel have potent antiangio-genic activities, which may explain their efficacy onKaposi lesions.11,12 Sgadari et al.13 showed that pacli-taxel down-regulates Bcl-2 anti-apoptotic effect andblocks the growth, migration, and invasion of KS cellsin vitro. It also promotes the regression of KS lesionsin mice. Docetaxel appears to be an even more potentangiogenesis inhibitor (from 4-fold to 10-fold) thanpaclitaxel.11,12

The efficacy of paclitaxel given as second-line orthird-line therapy has been evaluated well in associa-tion with highly active antiretroviral therapy in pa-

1786 CANCER April 15, 2006 / Volume 106 / Number 8

TABL

E1

Patie

ntCh

arac

teri

stic

s

Patie

nt(T

ype

ofKS

)

Tim

eof

KSEv

olut

ion

atTa

xane

Initi

atio

nPr

evio

usTh

erap

yTa

xane

(No.

ofIn

fusio

ns)

Effic

acy

(ACT

GCr

iteria

)De

sinfil

trat

ion

ofKS

Lesio

ns

Impr

ovem

ent

of Lym

phed

ema

Clin

ical

tole

ranc

eBi

olog

icTo

lera

nce

Follo

w-U

pW

ithou

tRe

curr

ence

Last

Eval

uatio

n

1(E

ndem

ic)

1Y

IFN

�D

ocet

axel

(8)

Parti

alCo

mpl

ete

Mar

ked

Mild

naus

eaGr

ade

lneu

trope

nia;

MPC

,102

0/m

m3 ;

leno

gras

tim;G

rade

1th

rom

bope

nia

(97

000/

mm

3 )

18M

osRe

curr

ence

,rei

ntro

duct

ion

ofdo

ceta

xel:

resp

onse

2(E

ndem

ic)

8Y

Bleo

myc

in,

vepe

side,

IFN

�Pa

clita

xel(

9)Pa

rtial

Parti

alM

arke

dM

ildna

usea

Good

,MPC

�15

00/

mm

34

Mos

Recu

rren

ce,r

eint

rodu

ctio

nof

pacl

itaxe

l,fa

ilure

3(C

lass

ic)

6Y

IFN

�,ga

ncyc

lovi

rpl

usrib

aviri

n,im

iqui

mod

Doc

etax

el(3

)Pa

rtial

Com

plet

eM

arke

dGo

odGo

od,M

PC�

1500

/m

m3

20M

osN

ore

curr

ence

4(P

osttr

ansp

lant

atio

n)1

YBl

eom

ycin

Doc

etax

el(2

)Pa

rtial

Com

plet

eSt

able

Grad

e1

diar

rhea

,m

yalg

ia

Good

,MPC

�15

00/

mm

325

Mos

Mild

recu

rren

ce,n

otre

atm

ent

5(E

ndem

ic)

10Y

Vinb

last

ine,

vepe

side,

IFN

�,bl

eom

ycin

,da

unor

ubic

in

Pacl

itaxe

l(7)

Parti

alPa

rtial

Mild

Good

Good

,MPC

�15

00/

mm

317

Mos

No

recu

rren

ce17

mon

ths

afte

rthe

end

oftre

atm

enta

ndlo

stto

follo

w-u

p6

(Cla

ssic

)8

YIF

N�,

vinb

last

ine,

bleo

myc

inD

ocet

axel

(3)

Parti

alPa

rtial

Parti

alGo

odGo

od,M

PC,

1353

/mm

32

Mos

Recu

rren

ce;s

witc

hed

topa

clita

xel(

2co

urse

s);

resp

onse

7(C

lass

ic)

5Y

IFN

�,do

xoru

bici

nD

ocet

axel

(3)

Parti

alPa

rtial

Parti

alGo

odGo

od,M

PC�

1500

/m

m3

Und

ertre

atm

ent

NA

8(C

lass

ic)

8Y

Vinb

last

ine,

Adria

myc

in,

doxo

rubi

cin

Doc

etax

el(8

)Pa

rtial

Com

plet

eM

arke

dGo

odGr

ade

3ne

utro

peni

a;M

PC,6

95/m

m3

8M

osN

ore

curr

ence

9(C

lass

ic)

4Y

Vinb

last

ine,

IFN

�,da

unor

ubic

inD

ocet

axel

(14)

Parti

alCo

mpl

ete

Mar

ked

Good

Grad

e4

neut

rope

nia;

MPC

,250

/mm

3 ;le

nogr

astim

14M

osRe

curr

ence

;rei

ntro

duct

ion

ofdo

ceta

xel;

resp

onse

10(C

lass

ic)

3Y

Vinb

last

ine,

doxo

rubi

cin

Doc

etax

el(8

)Pa

rtial

Com

plet

eM

arke

dGo

odGo

od,M

PC�

1500

/m

m3 ;l

enog

rast

im9

Mos

No

recu

rren

ce

11(C

lass

ic)

6M

osN

one

Pacl

itaxe

l(6)

Parti

alPa

rtial

Mild

Good

Good

,MPC

�15

00/

mm

3U

nder

treat

men

tN

A

12(E

ndem

ic)

10Y

Bleo

myc

in,

vinb

last

ine

Doc

etax

el(6

)Pa

rtial

Parti

alM

ildGo

odGr

ade

3ne

utro

peni

a;M

PC,8

70/m

m3 ;

leno

gras

tim

Und

ertre

atm

ent

NA

KS:K

apos

isar

com

a;AC

TG:A

IDS

Clin

icalT

rials

Grou

p;IF

N�:i

nter

fero

n�

MPC

:min

imal

polyn

uclea

rcou

nt;N

A:no

tapp

licab

le;Y:

year

;Mos

:mon

ths.

Non-HIV-Associated KS Treated with Taxanes/Fardet et al. 1787

tients with AIDS-related KS. In a large published study(107 patients), a complete or partial response wasachieved by 56% of patients.14 The onset of responsegenerally was rapid (median, 1.6 months; range, 1.2-1.8 months), and the response duration was prolonged(median, 8.9 months; range, 6.8-11.2 months). Twosmaller studies focused on the efficacy of docetaxel. Inthe first of those studies, Autier et al.15 reported apartial or complete response in 7 of 9 anthracycline-pretreated patients with AIDS-related cutaneous orvisceral KS who were treated with 60 mg/m2 or 75mg/m2 docetaxel every 3 weeks. In the study by Lim etal.,16 12 patients were treated with docetaxel at 25mg/m2 weekly for 8 weeks (as second-line therapy for10 patients). A partial response was achieved by 42%of their patients, In those studies, clinical tolerancewas acceptable, except for Grade 3 or 4 neutrope-nia.14,15 Our protocol (1 treatment every 3 weeks) and

the absence of preexisting leukopenia in our popula-tion (compared with chronic HIV-infected patients)may explain the better biologic tolerance we observeddespite our elderly population.

Before the current study, the efficacy of these mol-ecules in non-HIV-associated forms of KS had beenevaluated poorly. Only a few case reports are availablein the medical literature,3–7 and those concern pa-tients with posttransplantation KS (n � 2 patients)and classic KS (n � 3 patients) who were treated withpaclitaxel. In those studies, the infusion protocol dif-fered from that used in the current work, with lowerweekly dose infusions. However, the efficacy of pacli-taxel in those studies was similar to ours, with a partial(or complete), rapid, and prolonged response achievedby in patients.

In conclusion, the current results suggest that tax-anes are highly active in patients with non-HIV asso-ciated KS. These drugs should be considered either asa first-line, short-duration therapy in severely disabledpatients or as a second-line therapy after interferonand/or vinblastine failure.

REFERENCES1. Costa da Cunha CS, Lebbe C, Rybojad M, et al. Long-term

follow-up of non-HIV Kaposi’s sarcoma treated with low-dose recombinant interferon alfa-2b. Arch Dermatol. 1996;132:285-290.

2. Tur E, Brenner S. Classic Kaposi’s sarcoma: low-dose inter-feron alfa treatment. Dermatology. 1998;197:37-42.

3. Patel N, Salifu M, Sumrani N, et al. Successful treatment ofpost-renal transplant Kaposi’s sarcoma with paclitaxel. Am JTransplant. 2002;2:877-879.

4. Engin H, Celik I. Treatment of classical Kaposi’s sarcomawith visceral involvement by weekly paclitaxel. Clin Oncol (RColl Radiol). 2002;14:178.

5. Chao SC, Lee JY, Tsao CJ. Treatment of classical type Kapo-si’s sarcoma with paclitaxel. Anticancer Res. 2001;21(1B):571-573.

FIGURE 1. Patient 10 before treatment with docetaxel.

FIGURE 2. Patient 10 after 3 infusions of docetaxel.

FIGURE 3. Patient 10 after 8 infusions of docetaxel.

1788 CANCER April 15, 2006 / Volume 106 / Number 8

6. Wu CJ, Scadden DT. Posttransplant Kaposi’s sarcomatreated with paclitaxel. J Clin Oncol. 1998;16:3478-3479.

7. Stoebner PE, Nocera T, Meynadier J, Meunier L. Efficacy ofdocetaxel in disseminated classical Kaposi’s sarcoma. Br JDermatol. 2000;143:1357-1359.

8. Krown SE, Testa MA, Huang J. AIDS-related Kaposi’s sar-coma: prospective validation of the AIDS Clinical TrialsGroup staging classification. AIDS Clinical Trials Group On-cology Committee. J Clin Oncol. 1997;15:3085-3092.

9. National Cancer Institute, Cancer Therapy Evaluation Pro-gram. Common terminology criteria for adverse events, ver-sion 3.0. Available at URL: http://ctep.cancer.gov [accessedMarch 1, 2006].

10. Iscovich J, Boffetta P, Franceschi S, Azizi E, Sarid R. ClassicKaposi sarcoma: epidemiology and risk factors. Cancer.2000;88:500-517.

11. Grant DS, Williams TL, Zahaczewsky M, Dicker AP. Com-

parison of antiangiogenic activities using paclitaxel (taxol)and docetaxel (taxotere). Int J Cancer. 2003;104:121-129.

12. Vacca A, Ribatti D, Iurlaro M, et al. Docetaxel versus pacli-taxel for antiangiogenesis. J Hematother Stem Cell Res. 2002;11:103-118.

13. Sgadari C, Toschi E, Palladino C, et al. Mechanism of paclitaxelactivity in Kaposi’s sarcoma. J Immunol. 2000;165:509-517.

14. Tulpule A, Groopman J, Saville MW, et al. Multicenter trial oflow-dose paclitaxel in patients with advanced AIDS-relatedKaposi sarcoma. Cancer. 2002;95:147-154.

15. Autier J, Picard-Dahan C, Marinho E, et al. Docetaxel inanthracycline-pretreated AIDS-related Kaposi’s sarcoma: aretrospective study. Br J Dermatol. 2005;152:1026-1029.

16. Lim ST, Tupule A, Espina BM, Levine AM. Weekly docetaxelis safe and effective in the treatment of advanced-stageacquired immunodeficiency syndrome-related Kaposi sar-coma. Cancer. 2005;103:417-421.

Non-HIV-Associated KS Treated with Taxanes/Fardet et al. 1789