Liposomal doxorubicin: a phase II trial.

Abstract

In patients with disseminated endometrial carcinoma, doxorubicin is used as a single agent or in combination therapy. We have carried out a phase II clinical trial of liposomal doxorubicin in first-line therapy of women with disseminated endometrial carcinoma.
Between September 2001 and May 2003, 22 patients with histologically confirmed disseminated endometrial carcinoma, were enrolled in this study. Eleven patients had been previously treated with radiation, none of them had been treated with chemotherapy. Liposomal doxorubicin (40 mg/m2) was intravenously administered at 4 week intervals until toxicity or progression.
The most common adverse events were fatigue, anemia, pain, and dermatologic toxicity (EPP). Eight patients (36%) achieved a tumor regression (Complete response, CR 3; Partial response, PR 5), ten (46%) maintained stable disease, and four (18%) experienced increasing disease.
Liposomal doxorubicin has a lower cardiologic toxicity than doxorubicin with a similar response rate in patients with disseminated endometrial carcinoma.

Full text

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Introduction
In patients with disseminated endometrial carci-
noma,doxorubicin is used as a single agent or in com-
bination therapy (1). This agent is able to bind to
DNA and inhibit nucleic acid synthesis causing
DNA strand breaks by binding to topoisomerasi II as
it cleaves DNA. However, its cardiac toxicity is well
known. Liposomal doxorubicin, doxorubicin enca-
psulated in long-circulating liposomes, should have
less cardiac toxicity, but similar response rates compa-
red to standard doxorubicin. Liposomes are micro-
scopic vesicles composed of a phospholipid bilayer,
capable of encapsulating active drugs. The liposome
formulations incorporating a synthetic polyethylene
glycol-derivatized phospholipid, a process often re-
ferred to as pegylation, have a pronounced effect on
liposome tissue distribution and can produce a large
increase in the pharmacological efficacy of encapsula-
ted antitumor drugs. This effect is associated with a
more than 5-fold prolongation of liposome circula-
tion time in blood, a marked decrease in uptake by li-
ver and spleen, and an increased accumulation in tu-
mors (2, 3). Based on a previous study of the Gyne-
cologic Oncology Group (1), we carried out a phase
II clinical trial of liposomal doxorubicin in first-line
therapy of women with disseminated endometrial
carcinoma.
Materials and methods
Between September 2001 and May 2003, 22 pa-
tients with histologically confirmed disseminated en-
dometrial carcinoma, were enrolled in this study. All
cases presented stage III FIGO endometrioid carcino-
mas and peritoneal sierosa as the site of dissemination.
The patients had a median age of 50 years (ranged 40-
70). Eleven patients had been previously treated with
radiation, none of them had been treated with che-
motherapy. All patients provided written informed
consent. The main criteria of inclusion are summari-
Liposomal doxorubicin:a phase II trial
Giancarlo Balbi, Serena Visconti, Antonietta Monteverde, Maria-Amparo Manganaro,
Antonio Cardone
Department Obstetrics and Gynecology. Second University of Study of Naples, Naples, Italy
Abstract. Background and aim of the work:In patients with disseminated endometrial carcinoma,doxorubicin
is used as a single agent or in combination therapy. We have carried out a phase II clinical trial of liposomal
doxorubicin in first-line therapy of women with disseminated endometrial carcinoma. Methods: Between
September 2001 and May 2003, 22 patients with histologically confirmed disseminated endometrial carci-
noma, were enrolled in this study. Eleven patients had been previously treated with radiation, none of them
had been treated with chemotherapy. Liposomal doxorubicin (40 mg/m2) was intravenously administered at
4 week intervals until toxicity or progression. Results: The most common adverse events were fatigue, ane-
mia, pain, and dermatologic toxicity (EPP). Eight patients (36%) achieved a tumor regression (Complete re-
sponse, CR 3; Partial response, PR 5), ten (46%) maintained stable disease, and four (18%) experienced in-
creasing disease. Conclusion: Liposomal doxorubicin has a lower cardiologic toxicity than doxorubicin with a
similar response rate in patients with disseminated endometrial carcinoma. (www.actabiomedica.it)
Key words:Liposomal doxorubicin, endometrial cancer, toxicity
O R I G I N A L
A R T I C L E
ACTA BIOMED 2007; 78: 210-213© Mattioli 1885

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zed in table 1; the adverse events are calculated with
“Common Toxicity Criteria” (2.0 version, 23rd March
1998).
Liposomal doxorubicin (40 mg/m2) was intrave-
nously administered at 4 week intervals until toxicity
or progression. Patients, in which no tumor progres-
sion or intolerable toxicity was observed, received
maximum twenty cycles of the drug.
All patients were premedicated with steroids,an-
tihistamine, and cimetidyne considering that the lipo-
somal part of the molecule is allergenic.Cardioprotec-
tive agents were not used. The cardiac function was
monitored by cardiac ultrasound. The therapy was
continued until left ventricular ejection fraction was in
the normal range. Prior to the initial treatment and
during the treatment the patients were monitored as
reported in table 2.
Laboratory tests ( WBC, RBC, HB, PLT, serum
creatinine, total bilirubin, SGOT, SGPT, glucose le-
vels, nitrogen levels, iron levels) were performed every
week between consecutive cycles during the entire
therapy. In patients with diabetes (type 2) or with gli-
cemic intolerance, liposomal doxorubicin was diluted
in a sodium-chloride solution (usually, based on the
technical characteristics of the drug, liposomal doxo-
rubicin is diluted in a glucose solution at 5%).
Moreover CT or MRI was performed after the
third cycle, in order to evaluate the drug efficacy .
Response was defined as reported in table 3.
Results
Six patients had previously received pelvic radia-
tion, and five patients previously underwent extrapel-
vic radiation, both for a maximum of 60 Gy. In these
patients an increase of dermatologic toxicity (palmar-
plantar erythrodysesthesia, or EPP) was observed.
The most common adverse events were fatigue,
anemia, pain and, dermatologic toxicity (EPP). We
observed that, among these, EPP was the most com-
mon adverse event of liposomal doxorubicin treat-
ment, despite a treatment with B6 vitamin complex
which began a week before the first chemotherapy cy-
cle was continued until the end of therapy .Three pa-
tients had dark complexion associated with stomatitis
and four patients showed only palmar-plater dark
macule associated with paralgesia (Fig. 1). In this
group of patients with important dermatological
reactions (grade 4) liposomal doxorubicin (30 mg/m2)
was administered (dose reduction of 25%) every 4
weeks.
Eight patients (36%) achieved tumor regression
(CR 3; PR 5), ten (46%) maintained stable disease,
and four (18%) experienced increasing disease (Fig.2).
211
Liposomal doxorubicin: a phase II trial
Table 1. Main criteria of inclusion
Disseminated endometrial carcinoma
No CHT or RT for a previous malignancy
Measurable disease considered incurable following failure of lo-
cal therapeutic measures (surgery and/or radiation therapy)
Performance status 0-2 (ECOG)
WBC > 3000/µl; granulocytes >1500/µl; platelets > 100000/µl
Serum creatinine <1,5 mg/dl
Total bilirubin < 1,5 x normal; GOT, GPT < 3 x normal
Normal left ventricular ejection fraction
Table 2. Tests used to monitor patients
History and physical examination
PS, weight, body surface area
Serum creatinine, azotemia
Total bilirubin, SGOT, SGPT, blood glucose levels
Haemoglobin, WBC with differential count, platelets, iron
levels
CT or MRI for tumor assessment
Table 3. Definition of response
CR (complete response) No evidence of disease for > 12
weeks
PR (partial response)Reduction of > 50% of each lesion
for > 12 weeks
ID (increasing disease) Increase of > 50 % of any lesion
documented within 12 weeks of
study entry or the appearance of
any new lesion within 12 weeks
of study entry
SD (stable disease)Any condition meeting none of the
above criteria

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212
G.C. Balbi, V. Visconti, A. Monteverde, M-A. Amparo, A. Cardone
Discussion
We tested a first-line chemotherapy in dissemi-
nated endometrial carcinoma with the possibility that
liposomal doxorubicin could induce a higher response
rate than doxorubicin. In first-line therapy for meta-
static breast cancer, liposomal doxorubicin has the sa-
me efficacy of doxorubicin, with significantly reduced
cardiotoxicity,myelosuppression,vomiting,and alope-
cia: therefore it was necessary to assess the activity of
liposomal doxorubicin alone in disseminated endome-
trial carcinoma. In the Gynecologic Oncology Group
Study, the overall response rate (RR) with liposomal
doxorubicin was of 11,5% (1), while previous trials in-
dicated a first-line single agent response rate for doxo-
rubicin of 22-25% (4, 5) . In this study the overall RR
was of 36%.The overall response rates of other agents
(Paclitaxel, ifosfamide, cisplatin and vincristine) are
higher, as summarized in figure 3 (4, 6-10).
It is known that irreversible myocardial toxicity
leading to congestive heart failure is possible as the to-
tal dosage of doxorubicin approaches 550 mg/m2(11,
12). However, liposomal doxorubicin should not have
myocardial toxicity. In this study only two patients ex-
perienced cardiovascular toxicity. Moreover, the hae-
matological toxicity concerned red blood cells causing
serious anaemia (grade 3-4 in 5 patients: all patients
used hepoethyn molecules but 1 of them also needed
transfusions). These women presented fatigue which
is the most common adverse event in this disease.The
follow-up of the patients showed a gradual resolution
of dermatological adverse events only with the use of
B-complex vitamins.
In conclusion, liposomal doxorubicin shows a
lower cardiologic toxicity than doxorubicin with a si-
milar response rate in patients with disseminated en-
dometrial carcinoma. For this reason, liposomal doxo-
rubicin is preferable compared to the conventional
treatment. However, further studies are needed to in-
crease the drug tolerability especially at a dermatolo-
gical level.
References
1. Homesley HD, Blessing JA, et al. Phase II trial of liposomal
doxorubicin at 40 mg/m2every 4 weeks in endometrial car-
cinoma: a Gynecologic Oncology Group Study. Gynecologic
Oncology 2005; 98: 294-8.
2. Gabizon A, Barenhonz Y, Bialer M. Prolongation of the cir-
culation time of doxorubicin encapsulated in liposomes con-
taining a polyethylene glycol-derivatized phospholipid:phar-
macokinetic studies in rodents and dogs. Pharm Res 1993;
10: 703-8.
3. Gabizon A,Pappo O,Goren D,et al.Preclinical studios with
doxorubicin encapsulated in polyethylene-glycol coated lipo-
somes. J Liposome Res 1993; 3: 517-28.
Figure 1.Toxicity of grade 3-4 (CTC v. 2.0-NCIC-CTG)
Figure 2. Response rates.
Figure 3. First and second line response rates.

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Liposomal doxorubicin: a phase II trial
4.Thigpen JT, Brady MF, Homesley H, et al. Phase III trial of
doxorubicin with or without cisplatin in advanced endome-
trial carcinoma: a Gynecologic Oncology Group Study. J
ClinOncol 2004; 22: 3902-8.
5.Thigpen JT, Blessing JA, DiSaia PJ, et al. A randomized
comparison of doxorubicin alone versus doxorubicin plus cy-
clophosphamide in the management of recurrent endome-
trial carcinoma. A Gynecologic Oncology Group Study. J
Clin Oncol 1994; 12: 1408-14.
6.Thigpen JT, Blessing JA, Homesley H, et al. Phase II trial of
cisplatin as first-line chemotherapy in patients with advan-
ced or recurrent endometrial carcinoma. A Gynecologic On-
cology Group Study. Gynecol Oncol 1989; 33: 68-70.
7.Thigpen JT, Blessing JA, Lagasse LD, et al. Phase II trial of
cisplatin as second-line chemotherapy in patients with ad-
vanced or recurrent endometrial carcinoma: A Gynecologic
Oncology Group Study. Am J Clin Oncol 1984; 7: 253-6.
8. Brown GO, Blessing JA, Eddy GL, et al. A phase II trial of
vincristine given as a weekly intravenous bolus in advanced
or recurrent endometrial carcinoma. Am J Clin Oncol 1993;
16: 18-21.
9. Sutton GP, Blessing JA, DeMars LR, et al. A phase II Gy-
necologic Oncology Group trial of ifosfamide and mesna in
advanced or recurrent adenocarcinoma of the endome-
trium. Gynecol Oncol 1996; 63: 25-7.
10. Lincoln S, Blessing JA, Lee RB, et al. Activity of paclitaxel
as a second-line chemotherapy in endometrial carcinoma.
Gynecol Oncol 2003; 88: 277-81.
11. Muggia FM, Blessing JA, Sorosky J, et al. Phase II trial of
the pegylated liposomal doxorubicin in previously treated
metastatic endometrial carcinoma: a Gynecologic Onco-
logy Group Study. J Clin Oncol 2002; 20: 2360-4.
12. Fleming GF, Brunetto VL, Cella D, et al. Phase III trial of
doxorubicin plus cisplatin with or without paclitaxel plus
filgrastim in advanced endometrial carcinoma: a Gyneco-
logic Oncology Group Study. J Clin Oncol 2004; 22: 2159-
66.
Accepted: 5th September 2007
Correspondence: Giancarlo Balbi
Department Obstetrics and Gynecology
Second University of Study of Naples
Via Cimarosa, 84
80127 Napoli
Tel./Fax: 0815665598.
E-mail: giancarlo.balbi@unina2.it, www.actabiomedica.it