www.elsevier.com/locate/ygyno

Gynecologic Oncology

Temozolomide in uterine leiomyosarcomas

Sibyl Anderson*, Carol Aghajanian

Developmental Chemotherapy, Gynecology Disease Management Team, Memorial Sloan-Kettering Cancer Center,

Gynecology/Breast Services Academic Office, 1275 York Avenue, MRI-1027, New York, NY 10021, USA

Received 21 December 2004

Available online 23 May 2005

Abstract

Objective. Temozolomide has been studied in soft-tissue sarcomas with varying dosing schedules. We review the Memorial Sloan-

Kettering Cancer Center (MSKCC) experience in women with metastatic or unresectable leiomyosarcoma treated with continuous daily dose

(CDD) or bolus-dose (BD) temozolomide. We include a literature review of temozolomide activity in leiomyosarcoma patients.

Methods. After obtaining Institutional Review Board approval, we identified women with recurrent leiomyosarcoma treated with

temozolomide at MSKCC from 9/2001 to 9/2004. Patients were treated daily with dosages ranging from 50 to 75 mg/m2 for 6 out of 8 weeks

or for 5 days every 4 weeks with 150–300 mg/m2 daily. All patients were evaluated at least every month for toxicity and response. We

reviewed patients’ charts for age at diagnosis, stage, performance status, prior treatments, temozolomide dose and schedule, best response to

treatment, and treatment delays or dose reductions due to toxicity.

Results. Twelve patients were treated with CDD temozolomide (median age, 54 years; range, 35–72 years). All patients had previously

received doxorubicin; 11 had received �2 previous chemotherapy regimens. One patient achieved a prolonged partial response for 4 cycles; 4

demonstrated stabilization of disease for 2–5+ cycles.

Seven patients were treated with BD temozolomide (median age, 50 years; range, 43–63 years). All patients received previous

doxorubicin and received �2 previous chemotherapy regimens. Four patients achieved stabilization of disease for 3, 5, 6, and 16 cycles,

respectively. One patient achieved a near complete response for 13 cycles and continues to be followed off therapy for 10+ months.

Conclusions. Temozolomide has promising therapeutic benefit and is well tolerated in patients with metastatic unresectable

leiomyosarcoma. Further investigation of temozolomide in leiomyosarcoma patients is warranted.

D 2005 Elsevier Inc. All rights reserved.

Keywords: Temozolomide; Uterine leiomyosarcomas

Introduction

Uterine leiomyosarcomas are rare smooth-muscle tumors

accounting for less than 2–3% of all uterine malignancies

[1]. Standard therapy for uterine leiomyosarcoma is total

abdominal hysterectomy [2]. Although approximately half

of women will present with disease confined to the uterus,

the majority of patients will experience recurrence of

disease. This aggressive malignancy has a poor prognosis

with 5-year overall survival of less than 50% [3].

0090-8258/$ - see front matter D 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.ygyno.2005.03.018

* Corresponding author. Fax: +1 212 717 3214.

E-mail address: gynbreast@mskcc.org (S. Anderson).

Limited chemotherapeutic options are available for

patients presenting with metastatic or unresectable leiomyo-

sarcoma. The most commonly used agents include doxor-

ubicin [4], dacarbazine (DTIC) [5], gemcitabine [6], and

ifosfamide [7]. Each of these agents has a response rate of

less than 20% and a duration of response of less than 6

months. Although combination regimens may have slightly

higher response rates, the duration of response is still less

than 6 months. For example, Memorial Sloan-Kettering

Cancer Center’s (MSKCC’s) phase II trial of gemcitabine

and docetaxel in leiomyosarcoma patients has a published

response rate of 53% [8]. Unfortunately, the median

duration of response is less than 6 months. Clearly improved

98 (2005) 99 – 103

Table 1

Patient characteristics

Characteristic Dosing schedule continuous

Continuous Bolus

Patients (n) 12 7

Median age, years (range) 54 (35–72) 50 (43–63)

Karnofsky performance status,

median percentage (range)

80 (70–90) 80 (70–90)

Prior radiation therapy

Yes 3 1

No 9 7

Prior chemotherapy regimen

1 1 0

2 10 5

3 or more 1 2

Previous doxorubicin

chemotherapy

Yes 12 7

No 0 0

High pathologic grade 11 7

S. Anderson, C. Aghajanian / Gynecologic Oncology 98 (2005) 99–103100

chemotherapeutic agents are needed for patients presenting

with advanced or unresectable disease.

Temozolomide is a novel oral alkylating agent with similar

mechanism of action and structure to DTIC. It has demon-

strated efficacy in melanoma, glioblastoma, and mycosis

fungoides. Various doses and schedules have been inves-

tigated. Trials of continuous-dose temozolomide have

observed greater drug exposure compared with the every-4-

week bolus dosing [9]. Recent phase I/II trials of continuous-

dose temozolomide report a promising anti-tumor response

[10]. It is hypothesized that the continuous dosing schedule

may lessen the opportunity for developing drug resistance.

Given the limited chemotherapy options available,

salvage therapy for patients with advanced or metastatic

leiomyosarcoma remains a treatment dilemma for oncolo-

gists. Previous investigations of temozolomide suggest

promising activity in specific subsets of soft-tissue sarcoma,

specifically leiomyosarcomas. We report our retrospective

investigation of a heavily pretreated group of metastatic

unresectable leiomyosarcoma patients treated with bolus

and continuous-low-dose temozolomide at our institution,

and we review the literature.

Materials and methods

After Institutional Review Board approval was obtained,

we reviewed our database of patients with recurrent or

metastatic unresectable leiomyosarcoma treated by

MSKCC’s Developmental Chemotherapy Service with

continuous-low-dose or bolus temozolomide between Octo-

ber 2001 and June 2004. Patients were treated with 50–75

mg/m2 daily for 6 weeks followed by a 2-week rest, or 150–

300 mg/m2 daily for 5 days every 4 weeks. Patients’ charts

were reviewed for age at diagnosis, stage, performance

status, prior treatments, temozolomide dose and schedule,

best response to treatment, and treatment delays or dose

reductions due to toxicity. We performed a review of the

literature pertaining to temozolomide in leiomyosarcomas.

Responses were evaluated via CT scan. Response was

assessed according to Response Evaluation Criteria in Solid

Tumors criteria [11].

Results

Continuous dose

Twelve patients were treated with continuous low-dose

temozolomide as described. Their characteristics are shown

in Table 1. All patients had recurrent or metastatic leiomyo-

sarcoma. Patients had amedian age of 54 years (range, 35–72

years) and median Karnofsky performance status of 80%

(range, 70–90%). All 12 patients had previously received

doxorubicin-based chemotherapy. The majority of patients

(10/12, 83%) had metastatic or recurrent disease to the lungs.

Three patients had previously received radiation. Patients had

a median of 2 previous treatments prior to temozolomide.

Twenty-five cycles of temozolomide were given to 12

patients (median, 1 cycle; range, 1–5+). No patient required

hospitalization for treatment-related toxicity. The most

commonly reported side effect was nausea or vomiting,

which was well controlled with oral anti-emetics. There

were no treatment-related deaths, transfusions, neutropenia,

or episodes of neutropenic fever. No procrit support was

required. One patient required dose reduction.

One patient had a partial response. Response duration

was 4 months. Her case is reported in further detail (case 1).

Four patients demonstrated stable disease and 7 patients

progressed while on therapy. One patient who experienced

stable disease after 2 cycles of therapy did not continue

treatment secondary to complications from doxorubicin-

associated class III heart failure. One patient with stable

disease continues on treatment after 5 cycles of therapy. One

patient with overall disease progression in the abdominal

and pelvic disease had metastases to skin that completely

resolved. See Table 2 for patient disposition.

Bolus dose

Seven patients were treated with bolus-dose temozolo-

mide as described. Patient characteristics are shown in Table

1. All patients had recurrent or metastatic leiomyosarcoma.

Patients had a median age of 50 years (range, 43–63 years)

and median Karnofsky performance status of 80% (range,

70–90%). All 7 patients received previous doxorubicin-

based chemotherapy. Four (57%) patients had metastatic or

recurrent disease involving the lungs. One patient received

previous radiation. Patients had a median of 3 previous

treatments prior to temozolomide.

Forty-six cycles of bolus temozolomide treatment were

given to 7 patients (median, 5 cycles; range, 1–16). No

patient required hospitalization for treatment-related toxicity.

Table 2

Outcome of temozolomide: patient disposition: continuous dose

Patient Stage Prior XRT No. of prior chemotherapy Metastatic sites KPS Initial dose Number cycles Best response

1 I NO 2 LNG 90 75 4 PR

2 I NO 2 LNG, B, PLVS 80 50 2 SD

3 VI NO 2 LNG 80 50 1 POD

4 I YES 2 LNG 80 50 1 POD

5 VI NO 2 LNG 90 75 5 SD

6 I NO 2 PLVS 80 50 1 POD

7 VI YES 2 B, LNG 80 50 2 SD

8 III NO 2 PLVS 80 75 1 POD

9 VI NO 2 LNG 90 75 1 POD

10 I YES 2 SKIN, PLVS 80 50 1 POD

11 VI NO 2 LNG 90 75 1 POD

12 I NO 5 LNG 90 75 5+ SD

B, bone; KPS, Karnofsky performance status; LNG, lung; PLVS, pelvis; PR, partial response; SD, stable disease; POD, progression of disease; XRT, radiation

therapy.

S. Anderson, C. Aghajanian / Gynecologic Oncology 98 (2005) 99–103 101

The most commonly reported side effect was nausea or

vomiting, which was well controlled with oral anti-emetics.

There were no treatment-related deaths, neutropenia, or

episodes of neutropenic fever. One patient required trans-

fusion for asymptomatic anemia believed related to previous

therapy. One patient had a near complete response to

treatment for 13 cycles of therapy and continues to be

followed off therapy for over 10 months. Her case is

presented in further detail (case 2). Four patients experienced

stable disease for 3, 5, 6, and 16 cycles, respectively. Three

patients progressed while on therapy. See Table 3 for patient

disposition.

Case study 1: Continuous daily dose

A forty-six-year-old nulliparous female was diagnosed

with a high-grade uterine leiomyosarcoma confined to the

uterine corpus. She underwent total abdominal hysterec-

tomy/bilateral salpingo-oophorectomy (TAH/BSO) fol-

lowed by 6 cycles of adjuvant doxorubicin and ifosfamide

without complication. Six months later, the patient relapsed

with bilateral pulmonary metastases. Her disease continued

to progress despite treatment with a clinical trial of

gemcitabine and docetaxel. She was followed with expect-

ant observation for 3 months. Her CT scan then revealed

several increasing bilateral pulmonary nodules, the largest

of these in the right lung base, measuring 2.8 cm, and in the

Table 3

Outcome of temozolomide: patient disposition: bolus dose

Patient Stage Prior XRT No. of prior

chemotherapy

Metastati

1 III NO 2 PLS

2 I NO 2 PLVS

3 III YES 2 PLVS

4 I NO 6 LNG

5 VI NO 2 LNG

6 VI NO 3 LNG

7 VI NO 2 LVR, LN

B, bone; CR, complete response; KPS, Karnofsky performance status; LNG, lung;

XRT, radiation therapy.

left lung, measuring 1.8 cm. There was no disease involving

the abdomen or pelvis. After 1 cycle of temozolomide, her

CT revealed tumor regression with the right lung-base

nodule measuring 1 cm and the left mass 0.6 cm. She

achieved partial remission with 4 cycles of therapy. She

subsequently progressed with enlargement of the right lung

mass compressing the right bronchial tree and obliteration of

the left lower lobe bronchus. She initiated palliative

radiation therapy but was hospitalized for progressive

symptomatic disease and placed on hospice. She passed

away on home hospice approximately 16 weeks after her

last dose of temozolomide.

Case study 2: Bolus dose

A sixty-three-year-old multiparous female was diagnosed

with a high-grade uterine leiomyosarcoma confined to the

uterine corpus. She underwent total abdominal hysterec-

tomy/bilateral salpingo-oophorectomy (TAH/BSO). Post-

operative CT scan revealed a right lower lobe nodule, which

was resected. Three months later, CT scan revealed multiple

bilateral pulmonary nodules. She was treated with doxor-

ubicin for 5 cycles, to which she achieved a partial response,

and was followed with expectant observation for 3 months

until she progressed in the lungs. She then progressed to

treatment with ifosfamide, and then gemcitabine. She was

then treated with temozolomide without complication for 13

c sites KPS Initial dose Number

cycles

Best

response

70 150 2 POD

80 150 1 POD

80 150 3 SD

80 150 6 SD

90 150 5 SD

80 200 13 CR

G 80 200 16 SD

LVR, liver; PLVS, pelvis; POD, progression of disease; SD, stable disease;

S. Anderson, C. Aghajanian / Gynecologic Oncology 98 (2005) 99–103102

cycles. CT scan showed a decrease in her largest nodule in

the right upper lobe from 1.3 to 0.5 cm, with shrinkage of

the remainder of her lung lesions to 1–2 mm in size. The

patient continues to be followed with expectant observation

and is without disease progression at over 10 months.

Discussion

There is an increasing body of evidence supporting the

variable response of various soft-tissue sarcoma subtypes

[12]. Given the relative chemoresistance of soft-tissue

sarcomas, stable disease and time to progression may well

indicate a significant response and therefore may be a

more appropriate therapeutic end point. Although our

small retrospective investigation demonstrates a response

rate of 8% for patients treated with the continuous daily-

dose regimen and 14% for those treated with the bolus-

dose regimen, the stable disease rate is notable. For

patients undergoing continuous-dose temozolomide ther-

apy, 33% experienced stable disease for 2–5 or more

cycles; for those undergoing bolus treatment, 57% expe-

rienced stable disease for 3–16 cycles. In addition, many

patients preferred the outpatient oral regimen over intra-

venous chemotherapy, and there were no toxicity-associ-

ated admissions, deaths, neutropenia, or neutropenic fever

for either dosing schedule.

Bolus-dose temozolomide trials demonstrate modest

responses in various soft-tissue sarcoma trials. The Soft

Tissue and Bone Sarcoma Group of the European Organ-

ization for Research and Treatment of Cancer (EORTC)

evaluated 750 mg/m2 of oral temozolomide divided over 5

days every 4 weeks in 31 patients [13]. One partial response

for 8 cycles was observed in a patient with retroperitoneal

leiomyosarcoma metastatic to breast, skin, and liver. Nine

patients of varying histologies had stable disease, and the

remainder of patients progressed to therapy. The most

commonly reported non-hematologic toxicity was nausea

and vomiting. There were no episodes of neutropenic fever

or grade 3 or 4 hematologic toxicity. Talbot et al. [14]

treated 25 patients with various soft-tissue sarcomas with

twice daily temozolomide for 5 days every 4 weeks. Two

patients had partial responses (8%), 3 patients (12%)

experienced stable disease for over 6 months, and 2 patients

had mixed responses (8%). All of these responding patients

had either uterine or non-uterine leiomyosarcoma. There

were no treatment-related deaths or grade 4 toxicity

observed in this small study.

Phase II investigations of extended dosing temozolomide

schedules in various soft-tissue sarcomas also suggest

modest activity and minimal toxicity in leiomyosarcoma.

Trent et al. [15] evaluated patients with gastrointestinal

stromal tumors (GIST) and other soft-tissue sarcomas with

bolus-dose daily temozolomide for 21 days followed by 7

days of rest. Of 39 evaluable patients with non-GIST

tumors, 18 had metastatic leiomyosarcoma. Two responses

were (11%) observed in this subgroup. One partial response

lasting for 7 months was seen in a patient with metastatic

pelvic leiomyosarcoma to the lung. In addition, stable

disease was observed in 33% of patients. Ten percent of

patients experienced grade 3 or 4 hematologic toxicity.

Fatigue, observed in 14% of patients, was the most common

non-hematologic toxicity. The Spanish Group for Research

on Sarcomas (CTOS) [16] evaluated oral temozolomide

given at 75 mg/m2/day for 6 weeks followed by a 3-week

break in patients with various soft-tissue sarcomas. Of 27

evaluable patients, 4 had leiomyosarcoma. Two of 4 partial

responses were observed in leiomyosarcoma patients; these

responses lasted for 14 and 10+ months, respectively.

Unresectable metastatic leiomyosarcomas are aggressive

malignancies and ultimately uniformly fatal. Our inves-

tigation supports the tolerable toxicity profile and therapeu-

tic benefit of temozolomide in leiomyosarcomas observed in

previous investigations. This is a small retrospective

analysis of a heavily pretreated group of patients with

advanced leiomyosarcoma; therefore, we can make no

comparison of the respective dosing schedules. However,

standard dosing schedules are with bolus dosing. Our

investigation supports further study of temozolomide in

leiomyosarcomas.

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