# Phase II Study of Temozolomide and Thalidomide in

Authors: Michelle S. Boyar; Mary Hesdorffer; Mary Louise Keohan; Zhezhen Jin; Robert N. Taub
Journal: Sarcoma
 (2008)

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## Abstract

We assessed the efficacy of combined temozolomide and thalidomide in patients with unresectable or metastatic leiomyosarcoma in a phase II single-institution trial. Twenty-four patients were enrolled. Temozolomide (150 mg/m2/day for 7 days every other week) was administered with concomitant thalidomide (200 mg/day), and continued until unacceptable toxicity or disease progression. There were no complete responses and two (10%) partial responses. Five patients (24%) had stable disease for at least six months. Fourteen patients (67%) progressed after a median of two-month treatment. The median overall survival (twenty-two assessable patients) was 9.5 months [95% CI 7–28 months]. There were no treatment-related deaths or CTC grade 4 toxicities. Thirteen patients were dose-reduced or discontinued thalidomide due to toxicity. In conclusion, this combination of temozolomide and thalidomide provided disease stabilization in a subset of patients with advanced leiomyosarcoma. We hypothesize that temozolomide is the active agent in this regimen, and should be further studied.


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## Body

## 1. Introduction

Soft tissue sarcomas are rare tumors, representing
less than 1% of all new cancers diagnosed in the United States
each year [1]. Complete
surgical resection offers the best chance of cure for localized soft  tissue
sarcoma. Patients with unresectable or
metastatic disease have a median survival of approximately 12 months. Chemotherapy is the main treatment option for
these patients. Doxorubicin, ifosfamide,
and dacarbazine (DTIC) each have single-agent activity with response rates
approaching 20% [2–4]. When DTIC was
added to doxorubicin, the response rate and overall survival increased at the
cost of increased toxicity [5].The use of immunohistochemistry and genetic markers
to better define subsets of soft tissue sarcomas is changing the approach to
clinical trial design in soft tissue sarcoma.
There is increasing evidence that the different subtypes of soft tissue
sarcoma have distinct biologic characteristics which define metastatic
potential and response to therapy. The
remarkable activity of imatinib in patients with gastrointestinal stromal
tumors is proof of this principle [6]. Instead of large clinical trials which
include a variety of histologic subtypes, newer trials are limiting enrollment
to specific subtypes to assess response rates in a subset of patients. This has led to the identification of active
regimens for certain subtypes of soft tissue sarcoma. However, new therapies
are clearly needed for patients with advanced or metastatic leiomyosarcoma.Over 50 subtypes of soft tissue tumors have been
described in adults, and leiomyosarcomas are one of the most common malignant
soft tissue sarcomas in adults. Leiomyosarcomas
are derived from smooth muscle cells and can arise in any location. However,
more than half are located in retroperitoneal or intraabdominal sites [7].Temozolomide is a cytotoxic alkylating agent that
was developed as an oral and less toxic alternative to DTIC. Both temozolomide and DTIC exert their
antitumor effects through the formation of  5-3-methyl-1-triazenolimidazole-4
carboxamide (MTIC), the putative active chemical metabolite of DTIC  [8, 9].
Temozolomide has activity against malignant gliomas and metastatic melanoma
[10, 11]. Based on its similar mechanism of action to dacarbazine, temozolomide
has been evaluated in soft tissue sarcoma using a variety of dosing
schedules. In several studies which
included a variety of STS subtypes, all of the clinical benefit was seen in
patients with leiomyosarcoma [12–14].Thalidomide is an agent shown to be useful in a
variety of tumors. Its mechanisms of
action in cancer may be multiple, including direct cytotoxic, antiangiogenic,
and anti-inflammatory effects [15]. The combination of temozolomide and
thalidomide has shown promising activity in metastatic melanoma [16] and
metastatic neuroendocrine tumors [17], where it led to increased response rates
when compared to temozolomide as a single agent. We conducted this
single-institution phase II trial to assess the efficacy of a combination
regimen of temozolomide and thalidomide in patients with unresectable or
metastatic leiomyosarcoma.


## 2. Patients and Methods

### 2.1. Study Population

The study population consisted of adult patients
(age ≥18) with histologically confirmed, locally advanced,
unresectable or metastatic leiomyosarcoma.
Prior treatment with up to three prior systemic chemotherapy regimens
for advanced disease was permitted, as was previous dacarbazine treatment.
Prior radiation therapy was allowed if completed at least 4 weeks prior to
study drug administration. Patients were required to have at least one
unidimensional measurable lesion documented on computed tomography (CT).
Previously radiated lesions were excluded unless there was evidence of disease
progression at that site prior to enrollment. Further inclusion criteria
included: SWOG performance status of 0–2, life
expectancy >2 months, adequate bone marrow function (absolute neutrophil
count [ANC] ≥1500/μL, platelets >70 000/μL, and hemoglobin
≥10 g/dL), adequate hepatic function (bilirubin <  upper limit of
normal [ULN], AST or ALT <1.5 X ULN,
alkaline phosphatase <2 X ULN or ≤5 X ULN with documented liver
metastases), and adequate renal function (creatinine <1.5 X ULN, BUN <1.5
X ULN). Exclusion criteria included
brain metastases, more than 3 prior chemotherapy regimens for treatment of
leiomyosarcoma, insufficient recovery from toxicities of prior therapies, other
serious medical or psychiatric illness, inability to take oral medications,
prior malignancy other than curatively treated carcinoma in situ of the cervix
or skin cancer, and pregnant or nursing women.
Prior chemotherapy, radiation therapy or surgery must have been
completed at least four weeks prior to enrollment. All patients and physicians participated in
the Enhanced STEPS program (Enhanced System for Thalidomide Education and
Prescribing Safety). All patients gave
written informed consent before study entry.
The study was approved by the local institutional review board committee
and was conducted in accordance with the ethical principles stated in the
Declaration of Helsinki and the guidelines on good clinical practice.


### 2.2. Study Design

Patients received treatment with temozolomide at a
dose of150mg/m2/day orally on days 1 to 7 and days 15 to 21.
Thalidomide was administered daily at a dose of 200 mg. No dose escalations were permitted. Cycles
were repeated every 28 days. Temozolomide was held if ANC remained <1500/μL or
platelet count <100 000/μL, and was
not resumed until hematologic recovery. When treatment resumed, dose reductions
for temozolomide were made based on nadir platelet count or ANC. For nonhematologic toxicities of grade 3 or
higher as defined by the National Cancer Institute (NCI) Common Toxicity
Criteria (CTC) grading system, dosage for the subsequent cycle of temozolomide
was reduced to 125mg/m2 for grade 3 toxicity and to 100mg/m2 for grade 4 toxicity. No dose adjustments were required if the toxicity was
judged to be non-drug-related. Treatment was discontinued if the patient was
unable to resume therapy within three weeks or if they experienced unacceptable
toxicity levels. Dose modifications for thalidomide were made based on
thalidomide-related toxicity. When thalidomide-related toxicity was noted, the
dose of thalidomide was reduced to 100 mg daily; patients who experienced
toxicity at a dose of 100 mg were taken off thalidomide.Radiologic
assessments of all sites of measurable disease with CT scan were performed on
enrollment and every 8 weeks after starting treatment. Therapy was continued
until evidence of disease progression on CT scan, unacceptable drug toxicity,
delay of both drugs for >21 days, or patient-initiated withdrawal for any
reason. Standard World Health Organization (WHO) response criteria were used. A
complete response (CR) required complete disappearance of all clinically
detectable malignant disease for at least four weeks. A partial response (PR)
required ≥50% decrease in the sum of the products of the largest
perpendicular diameters of a measurable lesion.
Not all lesions had to show regression to qualify for partial response, but  no lesion should have increased by ≥25%, and no new lesions should have appeared. Stable disease (SD) was defined
as <50% decrease or <25% increase in the sum of the products of the
largest perpendicular diameters of all measurable lesions. Progression of disease (PD) was defined as a ≥25% increase in the sum of products of measurable lesions, clear worsening of
any evaluable disease, or appearance of any new lesions.


### 2.3. Statistical Analysis

This was an open-label, phase II study conducted at Columbia University Medical Center. The primary end point in this trial is
response (complete and partial response) rate. A response probability of 25%
would be of interest, while further testing would not be pursued if the
response probability was 5% or lower.
Initially, 15 patients would be entered. If at least one response was
observed, an additional 10 patients will be entered into the trial. Four or more responses out of a total of 25
patients would be considered as evidence warranting further study of this
regimen, provided that other factors, such as toxicity and survival were
favorable. This design has a
significance level (probability of falsely declaring an agent with a 5%
response probability to warrant further study) of 5%, and a power (probability
of correctly declaring an agent with a 25% response probability to warrant
further study) of 90%.Time to progression, overall survival, safety, and
toxicity were assessed as secondary outcomes.
Time to progression (date of initiation of treatment to date of
progression or death) and overall survival (time from treatment initiation to
the date of death) were assessed with Kaplan-Meier estimator. Toxicity and
complications of treatment were assessed based on patient reports of adverse
events, physical examination, and laboratory measurements.


## 2.1. Study Population

The study population consisted of adult patients
(age ≥18) with histologically confirmed, locally advanced,
unresectable or metastatic leiomyosarcoma.
Prior treatment with up to three prior systemic chemotherapy regimens
for advanced disease was permitted, as was previous dacarbazine treatment.
Prior radiation therapy was allowed if completed at least 4 weeks prior to
study drug administration. Patients were required to have at least one
unidimensional measurable lesion documented on computed tomography (CT).
Previously radiated lesions were excluded unless there was evidence of disease
progression at that site prior to enrollment. Further inclusion criteria
included: SWOG performance status of 0–2, life
expectancy >2 months, adequate bone marrow function (absolute neutrophil
count [ANC] ≥1500/μL, platelets >70 000/μL, and hemoglobin
≥10 g/dL), adequate hepatic function (bilirubin <  upper limit of
normal [ULN], AST or ALT <1.5 X ULN,
alkaline phosphatase <2 X ULN or ≤5 X ULN with documented liver
metastases), and adequate renal function (creatinine <1.5 X ULN, BUN <1.5
X ULN). Exclusion criteria included
brain metastases, more than 3 prior chemotherapy regimens for treatment of
leiomyosarcoma, insufficient recovery from toxicities of prior therapies, other
serious medical or psychiatric illness, inability to take oral medications,
prior malignancy other than curatively treated carcinoma in situ of the cervix
or skin cancer, and pregnant or nursing women.
Prior chemotherapy, radiation therapy or surgery must have been
completed at least four weeks prior to enrollment. All patients and physicians participated in
the Enhanced STEPS program (Enhanced System for Thalidomide Education and
Prescribing Safety). All patients gave
written informed consent before study entry.
The study was approved by the local institutional review board committee
and was conducted in accordance with the ethical principles stated in the
Declaration of Helsinki and the guidelines on good clinical practice.


## 2.2. Study Design

Patients received treatment with temozolomide at a
dose of150mg/m2/day orally on days 1 to 7 and days 15 to 21.
Thalidomide was administered daily at a dose of 200 mg. No dose escalations were permitted. Cycles
were repeated every 28 days. Temozolomide was held if ANC remained <1500/μL or
platelet count <100 000/μL, and was
not resumed until hematologic recovery. When treatment resumed, dose reductions
for temozolomide were made based on nadir platelet count or ANC. For nonhematologic toxicities of grade 3 or
higher as defined by the National Cancer Institute (NCI) Common Toxicity
Criteria (CTC) grading system, dosage for the subsequent cycle of temozolomide
was reduced to 125mg/m2 for grade 3 toxicity and to 100mg/m2 for grade 4 toxicity. No dose adjustments were required if the toxicity was
judged to be non-drug-related. Treatment was discontinued if the patient was
unable to resume therapy within three weeks or if they experienced unacceptable
toxicity levels. Dose modifications for thalidomide were made based on
thalidomide-related toxicity. When thalidomide-related toxicity was noted, the
dose of thalidomide was reduced to 100 mg daily; patients who experienced
toxicity at a dose of 100 mg were taken off thalidomide.Radiologic
assessments of all sites of measurable disease with CT scan were performed on
enrollment and every 8 weeks after starting treatment. Therapy was continued
until evidence of disease progression on CT scan, unacceptable drug toxicity,
delay of both drugs for >21 days, or patient-initiated withdrawal for any
reason. Standard World Health Organization (WHO) response criteria were used. A
complete response (CR) required complete disappearance of all clinically
detectable malignant disease for at least four weeks. A partial response (PR)
required ≥50% decrease in the sum of the products of the largest
perpendicular diameters of a measurable lesion.
Not all lesions had to show regression to qualify for partial response, but  no lesion should have increased by ≥25%, and no new lesions should have appeared. Stable disease (SD) was defined
as <50% decrease or <25% increase in the sum of the products of the
largest perpendicular diameters of all measurable lesions. Progression of disease (PD) was defined as a ≥25% increase in the sum of products of measurable lesions, clear worsening of
any evaluable disease, or appearance of any new lesions.


## 2.3. Statistical Analysis

This was an open-label, phase II study conducted at Columbia University Medical Center. The primary end point in this trial is
response (complete and partial response) rate. A response probability of 25%
would be of interest, while further testing would not be pursued if the
response probability was 5% or lower.
Initially, 15 patients would be entered. If at least one response was
observed, an additional 10 patients will be entered into the trial. Four or more responses out of a total of 25
patients would be considered as evidence warranting further study of this
regimen, provided that other factors, such as toxicity and survival were
favorable. This design has a
significance level (probability of falsely declaring an agent with a 5%
response probability to warrant further study) of 5%, and a power (probability
of correctly declaring an agent with a 25% response probability to warrant
further study) of 90%.Time to progression, overall survival, safety, and
toxicity were assessed as secondary outcomes.
Time to progression (date of initiation of treatment to date of
progression or death) and overall survival (time from treatment initiation to
the date of death) were assessed with Kaplan-Meier estimator. Toxicity and
complications of treatment were assessed based on patient reports of adverse
events, physical examination, and laboratory measurements.


## 3. Results and Discussion

### 3.1. Patient Characteristics

A total of 25 patients were entered on the study
from February 2002 to November 2004. One
patient was found to be ineligible and withdrawn from the study before
receiving therapy; that patient was excluded from the analysis. Demographics and baseline disease
characteristics for the 24 treated patients are presented in Table1. Patients had a median age of 60 years (range from
27 to 75 years); 22 (92%) were females and 2 (8%) males. Median SWOG performance status was 1. All
patients had biopsy-proven leiomyosarcoma.
The primary site was uterus in 11 (46%) of patients. Other primary sites included retroperitoneum
(n=3, 13%), small or large intestine (n=3, 13%), ovarian (n=1, 4%), and unknown
(n=3, 13%). All patients had evidence of
metastatic disease. Fifteen patients
(63%) had lung metastases and fourteen patients (58%) had liver
metastases. Eight patients (33%) had
metastases to bone or soft tissue.
Twenty patients (83%) had received prior chemotherapy, including treatment
with doxorubicin (n=16, 67%) and/or dacarbazine (n=4, 17%) and others. The median number of prior regimens was
2. Fourteen patients (58%) had prior
surgery, and three (13%) had prior radiation therapy.Table 1
Baseline patient characteristics.
CharacteristicsPatients (N=24)PercentNo.(%)Age, yearsMedian60Range27–75SexMale28Female2292SWOG performance status014118752520HistologyLeiomyosarcoma24100Primary siteUterus1146Retroperitoneum313Other1042Sites of metastasesLung1563Liver1458Other833Prior treatmentSurgery1458Radiotherapy313Chemotherapy2083Doxorubicin1567Dacarbazine417No. of prior chemo regimens0417162529383521


#### 3.2. Duration of Treatment

Of the 25 patients consented for the trial, 24
patients received treatment for a median of two months (range from 0.5 to 25
months) (Table2). Five patients received treatment for 6 months or more. Three
patients received treatment for less than 1 cycle due to rapidly progressive
disease (n=2), and withdrawal of consent (n=1).
Two patients required dose reduction of temozolomide due to neutropenia
and thrombocytopenia. Thirteen patients
required dose reduction of thalidomide (n=8) or discontinued thalidomide (n=5)
due to neuropathy or fatigue.Table 2
Response, location
of primary disease, prior therapy, and duration of therapy (days).
Enrolled patient ID No.ResponsePrimary site of diseasePrior chemotherapy regimensDuration of therapy (days)1PDColon
and duodenumDox342PDUterusDox/taxotere; Ifos/DTIC/etoposide; gleevec163PDUterusDox/ifex; gem/taxotere374PDStomachGleevec; ifex/dox85PDRetroperitonealDoxil; ifos; taxotere/gem; digitoxin256SDUnknownDox/ifex*114/3987PDIliopsoasDox; gem/taxotere428PRRetroperitonealNone*382/3899PDOvarianDoxo/ifex; gem/taxotere4510PDUterusDoxil, gem6211PDUterusGem/taxotere5612PDPelvic massGem/taxotere*36/6213PRUterusDox/ifos; gem/taxotere67014PDUnknownDTIC/doxo; gem/taxotere; digitoxin; ifos5015SDUterusDox/ifox/taxotere18616PDUterusGem/taxotere5217SDUterusDox; gem; taxotere14318SDUterusNone*157/20719PDColonNone3720PDUterusIfos; gem*30/5321PDKidneyNone7822PDSmall bowelDox/avastin; gem; DTIC5323SDRetroperitonealMAID; vin/doxo/cytoxan38324PDUterusGem/taxotere36*For the 5 patients who discontinued thalidomide early,
the fraction represents duration of therapy in days for Temodar + Thalidomide
over total days of therapy with Temodar.


#### 3.3. Toxicity

Twenty one patients were assessable for toxicity, which
is summarized in Table3. Grade 2 or 3
neutropenia developed in three patients (12%), and grade 2 or 3
thrombocytopenia developed in 4 patients (17%). Dose reduction of temozolomide
was required in 3 patients. Grade 2 or 3
anemia was seen in 3 patients. There
were no grade 4 hematologic toxicities.Table 3
Most common or serious hematologic and
nonhematologic toxicities.
ToxicityGrade 2Grade 3Grade 4No.%No.%No.%HematologicNeutropenia2814Thrombocytopenia31314Anemia2814Non-hematologicNausea833Emesis83328Fatigue125014Neurologic toxicity521312Constipation1042Anorexia521Edema313Fatigue was the most common nonhematologic toxicity
with grade 2 or 3 fatigue occurring in 13 (54%) patients, and attributed
primarily to thalidomide toxicity. Grade 2 or 3 nausea and emesis occurred in 8
(33%) and 10 (41%) of patients. Neurologic toxicity occurred in 8 patients and
was primarily neuropathy, however, one patient had grade 3 vision loss, and two
patients had grade 3 ataxia. Other
toxicities were relatively mild and consisted of grade 2 anorexia in five
patients (21%), grade 2 constipation in 10 patients (42%), and grade 2 edema in
three patients (13%). There were no
infectious complications due to treatment.


#### 3.4. Efficacy

Twenty one patients completed at least one cycle and
were assessable for treatment response.
There were no complete responses.
Two patients experienced durable partial responses. The overall
radiologic response rate was 10%. Five (24%) patients experienced stable
disease, and 14 (67%) had disease progression. The two patients with radiographic responses had durable responses
lasting 24 and 25 months before disease progression. For the five patients who had disease
stabilization, the median duration of stable disease was 15 months (range from 6
to 24 months). The median
follow-up time for the patient cohort is 41 months (range from 18 to 51
months). Twenty three  patients developed
progressive disease while receiving therapy, and the median progression-free
survival was 2 months with 95% CI (2 months–6 months) as
shown in Figure1. Twenty two patients are assessable for survival and the
median overall survival for the cohort is 9.5 months with 95% CI (7 months–28 months). The one-year survival rate was 40.9% with 95%
CI (24.8%, 67.6%), and the 2-year survival rate was 26.5% with 95% CI (13.1%,
53.9%) (Figure 2).Figure 1
Time to disease progression.Figure 2
Overall survival.The results of this study suggest that the
combination of temozolomide given on an alternating weekly schedule with daily
thalidomide has minimal clinical activity in patients with locally advanced or
metastatic leiomyosarcoma. Two (10%) out
of 21 patients evaluable for response had a partial response by WHO response
criteria. Five patients (24%) had
disease stabilization for at least 6 months while receiving treatment. The overall response rate in this study is
lower than what has been reported with DTIC alone [4]. Despite the low response
rate, both patients on this trial with radiographic responses had durable
responses lasting 24 and 25 months before disease progression. The median survival of 9.5 months is typical
for this advanced stage, heavily pretreated patient population.Temozolomide has been evaluated in soft tissue
sarcoma using several different dosing schedules. In our institution, a phase II trial enrolled
26 patients with unresectable or metastatic soft tissue sarcoma who were
treated with temozolomide administered twice daily on a 12-hour schedule for 5
days as an oral bolus dose of200mg/m2 followed by 9 doses of 90mg/m2 every four weeks. There were 2 partial
responses, 2 mixed responses, and 3 patients with stable disease lasting >6
months, for an overall objective response rate of 8%. All of the patients with clinical benefits
had leiomyosarcoma, none of the other soft tissue sarcoma histologic subtypes
had any benefit [12]. Another phase II study was conducted in 60 soft tissue
sarcoma patients (19 with GIST and 41 with other STS histologies). There were no responses seen in the patients
with GIST, and 22% had stable disease.
Of the evaluable patients with other soft tissue sarcomas, there was 1
CR and 1 PR for a total response rate of 5%, another 33% had stable
disease. The median time to progression
and median overall survival time in patients with other STS was 3.3 months and
11 months [13]. A phase II study by the
EORTC treated 31 patients with advanced STS with temozolomide dosed at 750mg/m2  over 5 days during cycle 1 and then 1000mg/m2 over 5 days at cycle
2. There was only 1 partial response for
an overall response rate of 3.33%. The
median TTP was 2 months and the median OS was 6.75 months [14].The Spanish Group for Research on Sarcomas conducted
a phase II trial of temozolomide given as daily for 6 weeks at a dose of75mg/m2/day–100mg/m2/day. They enrolled 49 patients with pretreated STS
and 18 patients with GIST. Among the
patients in the STS arm, there were 7 PR for an overall response rate of
15.5%. There were 11 patients with
gynecologic leiomyosarcoma enrolled, 5 of which showed response. The median
response duration was 12.5 months (range from 3.9 to 58 months). In 4 patients the response lasted over one
year. The median TTP was 2.2 months and
median OS was 8.1 months. The drug was well tolerated at this dose and grade 3-4 hematologic
toxicities were seen in 10–15% of
patients. This suggested that the
extended daily dosing schedule had activity in patients with gynecologic
leiomyosarcoma [18]. Memorial Sloan-Kettering published their experience with
temozolomide in patients with pretreated leiomyosarcoma from 2001 to 2004. Twelve patients were treated with continuous
daily dose temozolomide, there was one PR which lasted 4 cycles and 4 patients
had stabilization of disease from 2 to 5 cycles. Seven patients were treated with bolus dose
temozolomide. One patient had a near CR
which lasted 13 cycles and four patients had disease stabilization lasting from
3 to 16 cycles [19]. The collective
evidence from these phase II trials suggested that leiomyosarcomas,
particularly uterine leiomyosarcomas may be more responsive to treatment with
temozolomide than other STS histologic subtypes.In our study, enrollment was limited to patients
with leiomyosarcoma, but patients with leiomyosarcoma originating from any site
were eligible. Although there were only
two partial radiographic responses among the evaluable patients (10%), the
duration of response for both patients was prolonged, lasting 24 and 25 months,
respectively. Other groups have also
reported patients with durable responses lasting over 12 months [18]. The
significance of this finding in a disease where the median progression-free
survival ranges from two to three months suggests there is a cohort of
leiomyosarcoma patients who may derive significant benefit from treatment with
temozolomide.The relative contribution of thalidomide to the
antitumor efficacy in this study is difficult to determine. Although the reported toxicities were
generally mild, grade 2 thalidomide-related toxicities such as fatigue,
constipation, and neurologic toxicity were seen in up to 50% of patients. Dose reduction or discontinuation of
thalidomide was required in 13 (54%) of patients. Patients who continued treatment with
temozolomide had continued benefit even after stopping the thalidomide. We
concluded that thalidomide was poorly tolerated, and it is unlikely to add
additional antitumor efficacy in this patient population. Our results and those of other groups suggest
that temozolomide is the active agent in this regimen.


### 4. Conclusions

In conclusion, temozolomide offers another option to
consider in the treatment of patients with advanced or metastatic
leiomyosarcoma. Its benefits include the
convenience of oral administration and an improved side-effect profile compared
to traditional chemotherapy regimens for advanced soft tissue sarcoma. Although it does not produce high response
rates, there are a number of patients who have disease stabilization from
months to years even without radiographic responses. There are very few chemotherapy regimens that
offer the possibility of benefit in this patient population, and our data support
the consideration of temozolomide in the treatment of progressive disease. Although several dosing schedules have been
tested in trials (continuous daily dosing, bolus dosing and biweekly dosing),
there is not sufficient evidence to support adopting an alternative dosing
schedule, therefore, we recommend using the 5-day bolus dosing regimen for
temozolomide.Future investigation should focus on determining the
biologic and molecular characteristics of leiomyosarcomas that can predict
response to temozolomide. Methylation of the DNA repair protein
06-methylguanine-DNA-methyltransferase (MGMT) has been identified as a
predictor of response to temozolomide treatment in patients with glioblastoma
multiforme [20]. Epigenetic silencing
of MGMT and/or other key regulatory genes in tumor cells may play a role in
temozolomide resistance, and in the pathogenesis of soft tissue sarcomas. Because of the potential therapeutic benefits
to those patients who may respond to temozolomide, investigation of mechanisms
of response and resistance to this drug warrants further investigation in
leiomyosarcomas.


## 3.1. Patient Characteristics

A total of 25 patients were entered on the study
from February 2002 to November 2004. One
patient was found to be ineligible and withdrawn from the study before
receiving therapy; that patient was excluded from the analysis. Demographics and baseline disease
characteristics for the 24 treated patients are presented in Table1. Patients had a median age of 60 years (range from
27 to 75 years); 22 (92%) were females and 2 (8%) males. Median SWOG performance status was 1. All
patients had biopsy-proven leiomyosarcoma.
The primary site was uterus in 11 (46%) of patients. Other primary sites included retroperitoneum
(n=3, 13%), small or large intestine (n=3, 13%), ovarian (n=1, 4%), and unknown
(n=3, 13%). All patients had evidence of
metastatic disease. Fifteen patients
(63%) had lung metastases and fourteen patients (58%) had liver
metastases. Eight patients (33%) had
metastases to bone or soft tissue.
Twenty patients (83%) had received prior chemotherapy, including treatment
with doxorubicin (n=16, 67%) and/or dacarbazine (n=4, 17%) and others. The median number of prior regimens was
2. Fourteen patients (58%) had prior
surgery, and three (13%) had prior radiation therapy.Table 1
Baseline patient characteristics.
CharacteristicsPatients (N=24)PercentNo.(%)Age, yearsMedian60Range27–75SexMale28Female2292SWOG performance status014118752520HistologyLeiomyosarcoma24100Primary siteUterus1146Retroperitoneum313Other1042Sites of metastasesLung1563Liver1458Other833Prior treatmentSurgery1458Radiotherapy313Chemotherapy2083Doxorubicin1567Dacarbazine417No. of prior chemo regimens0417162529383521


### 3.2. Duration of Treatment

Of the 25 patients consented for the trial, 24
patients received treatment for a median of two months (range from 0.5 to 25
months) (Table2). Five patients received treatment for 6 months or more. Three
patients received treatment for less than 1 cycle due to rapidly progressive
disease (n=2), and withdrawal of consent (n=1).
Two patients required dose reduction of temozolomide due to neutropenia
and thrombocytopenia. Thirteen patients
required dose reduction of thalidomide (n=8) or discontinued thalidomide (n=5)
due to neuropathy or fatigue.Table 2
Response, location
of primary disease, prior therapy, and duration of therapy (days).
Enrolled patient ID No.ResponsePrimary site of diseasePrior chemotherapy regimensDuration of therapy (days)1PDColon
and duodenumDox342PDUterusDox/taxotere; Ifos/DTIC/etoposide; gleevec163PDUterusDox/ifex; gem/taxotere374PDStomachGleevec; ifex/dox85PDRetroperitonealDoxil; ifos; taxotere/gem; digitoxin256SDUnknownDox/ifex*114/3987PDIliopsoasDox; gem/taxotere428PRRetroperitonealNone*382/3899PDOvarianDoxo/ifex; gem/taxotere4510PDUterusDoxil, gem6211PDUterusGem/taxotere5612PDPelvic massGem/taxotere*36/6213PRUterusDox/ifos; gem/taxotere67014PDUnknownDTIC/doxo; gem/taxotere; digitoxin; ifos5015SDUterusDox/ifox/taxotere18616PDUterusGem/taxotere5217SDUterusDox; gem; taxotere14318SDUterusNone*157/20719PDColonNone3720PDUterusIfos; gem*30/5321PDKidneyNone7822PDSmall bowelDox/avastin; gem; DTIC5323SDRetroperitonealMAID; vin/doxo/cytoxan38324PDUterusGem/taxotere36*For the 5 patients who discontinued thalidomide early,
the fraction represents duration of therapy in days for Temodar + Thalidomide
over total days of therapy with Temodar.


### 3.3. Toxicity

Twenty one patients were assessable for toxicity, which
is summarized in Table3. Grade 2 or 3
neutropenia developed in three patients (12%), and grade 2 or 3
thrombocytopenia developed in 4 patients (17%). Dose reduction of temozolomide
was required in 3 patients. Grade 2 or 3
anemia was seen in 3 patients. There
were no grade 4 hematologic toxicities.Table 3
Most common or serious hematologic and
nonhematologic toxicities.
ToxicityGrade 2Grade 3Grade 4No.%No.%No.%HematologicNeutropenia2814Thrombocytopenia31314Anemia2814Non-hematologicNausea833Emesis83328Fatigue125014Neurologic toxicity521312Constipation1042Anorexia521Edema313Fatigue was the most common nonhematologic toxicity
with grade 2 or 3 fatigue occurring in 13 (54%) patients, and attributed
primarily to thalidomide toxicity. Grade 2 or 3 nausea and emesis occurred in 8
(33%) and 10 (41%) of patients. Neurologic toxicity occurred in 8 patients and
was primarily neuropathy, however, one patient had grade 3 vision loss, and two
patients had grade 3 ataxia. Other
toxicities were relatively mild and consisted of grade 2 anorexia in five
patients (21%), grade 2 constipation in 10 patients (42%), and grade 2 edema in
three patients (13%). There were no
infectious complications due to treatment.


### 3.4. Efficacy

Twenty one patients completed at least one cycle and
were assessable for treatment response.
There were no complete responses.
Two patients experienced durable partial responses. The overall
radiologic response rate was 10%. Five (24%) patients experienced stable
disease, and 14 (67%) had disease progression. The two patients with radiographic responses had durable responses
lasting 24 and 25 months before disease progression. For the five patients who had disease
stabilization, the median duration of stable disease was 15 months (range from 6
to 24 months). The median
follow-up time for the patient cohort is 41 months (range from 18 to 51
months). Twenty three  patients developed
progressive disease while receiving therapy, and the median progression-free
survival was 2 months with 95% CI (2 months–6 months) as
shown in Figure1. Twenty two patients are assessable for survival and the
median overall survival for the cohort is 9.5 months with 95% CI (7 months–28 months). The one-year survival rate was 40.9% with 95%
CI (24.8%, 67.6%), and the 2-year survival rate was 26.5% with 95% CI (13.1%,
53.9%) (Figure 2).Figure 1
Time to disease progression.Figure 2
Overall survival.The results of this study suggest that the
combination of temozolomide given on an alternating weekly schedule with daily
thalidomide has minimal clinical activity in patients with locally advanced or
metastatic leiomyosarcoma. Two (10%) out
of 21 patients evaluable for response had a partial response by WHO response
criteria. Five patients (24%) had
disease stabilization for at least 6 months while receiving treatment. The overall response rate in this study is
lower than what has been reported with DTIC alone [4]. Despite the low response
rate, both patients on this trial with radiographic responses had durable
responses lasting 24 and 25 months before disease progression. The median survival of 9.5 months is typical
for this advanced stage, heavily pretreated patient population.Temozolomide has been evaluated in soft tissue
sarcoma using several different dosing schedules. In our institution, a phase II trial enrolled
26 patients with unresectable or metastatic soft tissue sarcoma who were
treated with temozolomide administered twice daily on a 12-hour schedule for 5
days as an oral bolus dose of200mg/m2 followed by 9 doses of 90mg/m2 every four weeks. There were 2 partial
responses, 2 mixed responses, and 3 patients with stable disease lasting >6
months, for an overall objective response rate of 8%. All of the patients with clinical benefits
had leiomyosarcoma, none of the other soft tissue sarcoma histologic subtypes
had any benefit [12]. Another phase II study was conducted in 60 soft tissue
sarcoma patients (19 with GIST and 41 with other STS histologies). There were no responses seen in the patients
with GIST, and 22% had stable disease.
Of the evaluable patients with other soft tissue sarcomas, there was 1
CR and 1 PR for a total response rate of 5%, another 33% had stable
disease. The median time to progression
and median overall survival time in patients with other STS was 3.3 months and
11 months [13]. A phase II study by the
EORTC treated 31 patients with advanced STS with temozolomide dosed at 750mg/m2  over 5 days during cycle 1 and then 1000mg/m2 over 5 days at cycle
2. There was only 1 partial response for
an overall response rate of 3.33%. The
median TTP was 2 months and the median OS was 6.75 months [14].The Spanish Group for Research on Sarcomas conducted
a phase II trial of temozolomide given as daily for 6 weeks at a dose of75mg/m2/day–100mg/m2/day. They enrolled 49 patients with pretreated STS
and 18 patients with GIST. Among the
patients in the STS arm, there were 7 PR for an overall response rate of
15.5%. There were 11 patients with
gynecologic leiomyosarcoma enrolled, 5 of which showed response. The median
response duration was 12.5 months (range from 3.9 to 58 months). In 4 patients the response lasted over one
year. The median TTP was 2.2 months and
median OS was 8.1 months. The drug was well tolerated at this dose and grade 3-4 hematologic
toxicities were seen in 10–15% of
patients. This suggested that the
extended daily dosing schedule had activity in patients with gynecologic
leiomyosarcoma [18]. Memorial Sloan-Kettering published their experience with
temozolomide in patients with pretreated leiomyosarcoma from 2001 to 2004. Twelve patients were treated with continuous
daily dose temozolomide, there was one PR which lasted 4 cycles and 4 patients
had stabilization of disease from 2 to 5 cycles. Seven patients were treated with bolus dose
temozolomide. One patient had a near CR
which lasted 13 cycles and four patients had disease stabilization lasting from
3 to 16 cycles [19]. The collective
evidence from these phase II trials suggested that leiomyosarcomas,
particularly uterine leiomyosarcomas may be more responsive to treatment with
temozolomide than other STS histologic subtypes.In our study, enrollment was limited to patients
with leiomyosarcoma, but patients with leiomyosarcoma originating from any site
were eligible. Although there were only
two partial radiographic responses among the evaluable patients (10%), the
duration of response for both patients was prolonged, lasting 24 and 25 months,
respectively. Other groups have also
reported patients with durable responses lasting over 12 months [18]. The
significance of this finding in a disease where the median progression-free
survival ranges from two to three months suggests there is a cohort of
leiomyosarcoma patients who may derive significant benefit from treatment with
temozolomide.The relative contribution of thalidomide to the
antitumor efficacy in this study is difficult to determine. Although the reported toxicities were
generally mild, grade 2 thalidomide-related toxicities such as fatigue,
constipation, and neurologic toxicity were seen in up to 50% of patients. Dose reduction or discontinuation of
thalidomide was required in 13 (54%) of patients. Patients who continued treatment with
temozolomide had continued benefit even after stopping the thalidomide. We
concluded that thalidomide was poorly tolerated, and it is unlikely to add
additional antitumor efficacy in this patient population. Our results and those of other groups suggest
that temozolomide is the active agent in this regimen.


## 3.2. Duration of Treatment

Of the 25 patients consented for the trial, 24
patients received treatment for a median of two months (range from 0.5 to 25
months) (Table2). Five patients received treatment for 6 months or more. Three
patients received treatment for less than 1 cycle due to rapidly progressive
disease (n=2), and withdrawal of consent (n=1).
Two patients required dose reduction of temozolomide due to neutropenia
and thrombocytopenia. Thirteen patients
required dose reduction of thalidomide (n=8) or discontinued thalidomide (n=5)
due to neuropathy or fatigue.Table 2
Response, location
of primary disease, prior therapy, and duration of therapy (days).
Enrolled patient ID No.ResponsePrimary site of diseasePrior chemotherapy regimensDuration of therapy (days)1PDColon
and duodenumDox342PDUterusDox/taxotere; Ifos/DTIC/etoposide; gleevec163PDUterusDox/ifex; gem/taxotere374PDStomachGleevec; ifex/dox85PDRetroperitonealDoxil; ifos; taxotere/gem; digitoxin256SDUnknownDox/ifex*114/3987PDIliopsoasDox; gem/taxotere428PRRetroperitonealNone*382/3899PDOvarianDoxo/ifex; gem/taxotere4510PDUterusDoxil, gem6211PDUterusGem/taxotere5612PDPelvic massGem/taxotere*36/6213PRUterusDox/ifos; gem/taxotere67014PDUnknownDTIC/doxo; gem/taxotere; digitoxin; ifos5015SDUterusDox/ifox/taxotere18616PDUterusGem/taxotere5217SDUterusDox; gem; taxotere14318SDUterusNone*157/20719PDColonNone3720PDUterusIfos; gem*30/5321PDKidneyNone7822PDSmall bowelDox/avastin; gem; DTIC5323SDRetroperitonealMAID; vin/doxo/cytoxan38324PDUterusGem/taxotere36*For the 5 patients who discontinued thalidomide early,
the fraction represents duration of therapy in days for Temodar + Thalidomide
over total days of therapy with Temodar.


## 3.3. Toxicity

Twenty one patients were assessable for toxicity, which
is summarized in Table3. Grade 2 or 3
neutropenia developed in three patients (12%), and grade 2 or 3
thrombocytopenia developed in 4 patients (17%). Dose reduction of temozolomide
was required in 3 patients. Grade 2 or 3
anemia was seen in 3 patients. There
were no grade 4 hematologic toxicities.Table 3
Most common or serious hematologic and
nonhematologic toxicities.
ToxicityGrade 2Grade 3Grade 4No.%No.%No.%HematologicNeutropenia2814Thrombocytopenia31314Anemia2814Non-hematologicNausea833Emesis83328Fatigue125014Neurologic toxicity521312Constipation1042Anorexia521Edema313Fatigue was the most common nonhematologic toxicity
with grade 2 or 3 fatigue occurring in 13 (54%) patients, and attributed
primarily to thalidomide toxicity. Grade 2 or 3 nausea and emesis occurred in 8
(33%) and 10 (41%) of patients. Neurologic toxicity occurred in 8 patients and
was primarily neuropathy, however, one patient had grade 3 vision loss, and two
patients had grade 3 ataxia. Other
toxicities were relatively mild and consisted of grade 2 anorexia in five
patients (21%), grade 2 constipation in 10 patients (42%), and grade 2 edema in
three patients (13%). There were no
infectious complications due to treatment.


## 3.4. Efficacy

Twenty one patients completed at least one cycle and
were assessable for treatment response.
There were no complete responses.
Two patients experienced durable partial responses. The overall
radiologic response rate was 10%. Five (24%) patients experienced stable
disease, and 14 (67%) had disease progression. The two patients with radiographic responses had durable responses
lasting 24 and 25 months before disease progression. For the five patients who had disease
stabilization, the median duration of stable disease was 15 months (range from 6
to 24 months). The median
follow-up time for the patient cohort is 41 months (range from 18 to 51
months). Twenty three  patients developed
progressive disease while receiving therapy, and the median progression-free
survival was 2 months with 95% CI (2 months–6 months) as
shown in Figure1. Twenty two patients are assessable for survival and the
median overall survival for the cohort is 9.5 months with 95% CI (7 months–28 months). The one-year survival rate was 40.9% with 95%
CI (24.8%, 67.6%), and the 2-year survival rate was 26.5% with 95% CI (13.1%,
53.9%) (Figure 2).Figure 1
Time to disease progression.Figure 2
Overall survival.The results of this study suggest that the
combination of temozolomide given on an alternating weekly schedule with daily
thalidomide has minimal clinical activity in patients with locally advanced or
metastatic leiomyosarcoma. Two (10%) out
of 21 patients evaluable for response had a partial response by WHO response
criteria. Five patients (24%) had
disease stabilization for at least 6 months while receiving treatment. The overall response rate in this study is
lower than what has been reported with DTIC alone [4]. Despite the low response
rate, both patients on this trial with radiographic responses had durable
responses lasting 24 and 25 months before disease progression. The median survival of 9.5 months is typical
for this advanced stage, heavily pretreated patient population.Temozolomide has been evaluated in soft tissue
sarcoma using several different dosing schedules. In our institution, a phase II trial enrolled
26 patients with unresectable or metastatic soft tissue sarcoma who were
treated with temozolomide administered twice daily on a 12-hour schedule for 5
days as an oral bolus dose of200mg/m2 followed by 9 doses of 90mg/m2 every four weeks. There were 2 partial
responses, 2 mixed responses, and 3 patients with stable disease lasting >6
months, for an overall objective response rate of 8%. All of the patients with clinical benefits
had leiomyosarcoma, none of the other soft tissue sarcoma histologic subtypes
had any benefit [12]. Another phase II study was conducted in 60 soft tissue
sarcoma patients (19 with GIST and 41 with other STS histologies). There were no responses seen in the patients
with GIST, and 22% had stable disease.
Of the evaluable patients with other soft tissue sarcomas, there was 1
CR and 1 PR for a total response rate of 5%, another 33% had stable
disease. The median time to progression
and median overall survival time in patients with other STS was 3.3 months and
11 months [13]. A phase II study by the
EORTC treated 31 patients with advanced STS with temozolomide dosed at 750mg/m2  over 5 days during cycle 1 and then 1000mg/m2 over 5 days at cycle
2. There was only 1 partial response for
an overall response rate of 3.33%. The
median TTP was 2 months and the median OS was 6.75 months [14].The Spanish Group for Research on Sarcomas conducted
a phase II trial of temozolomide given as daily for 6 weeks at a dose of75mg/m2/day–100mg/m2/day. They enrolled 49 patients with pretreated STS
and 18 patients with GIST. Among the
patients in the STS arm, there were 7 PR for an overall response rate of
15.5%. There were 11 patients with
gynecologic leiomyosarcoma enrolled, 5 of which showed response. The median
response duration was 12.5 months (range from 3.9 to 58 months). In 4 patients the response lasted over one
year. The median TTP was 2.2 months and
median OS was 8.1 months. The drug was well tolerated at this dose and grade 3-4 hematologic
toxicities were seen in 10–15% of
patients. This suggested that the
extended daily dosing schedule had activity in patients with gynecologic
leiomyosarcoma [18]. Memorial Sloan-Kettering published their experience with
temozolomide in patients with pretreated leiomyosarcoma from 2001 to 2004. Twelve patients were treated with continuous
daily dose temozolomide, there was one PR which lasted 4 cycles and 4 patients
had stabilization of disease from 2 to 5 cycles. Seven patients were treated with bolus dose
temozolomide. One patient had a near CR
which lasted 13 cycles and four patients had disease stabilization lasting from
3 to 16 cycles [19]. The collective
evidence from these phase II trials suggested that leiomyosarcomas,
particularly uterine leiomyosarcomas may be more responsive to treatment with
temozolomide than other STS histologic subtypes.In our study, enrollment was limited to patients
with leiomyosarcoma, but patients with leiomyosarcoma originating from any site
were eligible. Although there were only
two partial radiographic responses among the evaluable patients (10%), the
duration of response for both patients was prolonged, lasting 24 and 25 months,
respectively. Other groups have also
reported patients with durable responses lasting over 12 months [18]. The
significance of this finding in a disease where the median progression-free
survival ranges from two to three months suggests there is a cohort of
leiomyosarcoma patients who may derive significant benefit from treatment with
temozolomide.The relative contribution of thalidomide to the
antitumor efficacy in this study is difficult to determine. Although the reported toxicities were
generally mild, grade 2 thalidomide-related toxicities such as fatigue,
constipation, and neurologic toxicity were seen in up to 50% of patients. Dose reduction or discontinuation of
thalidomide was required in 13 (54%) of patients. Patients who continued treatment with
temozolomide had continued benefit even after stopping the thalidomide. We
concluded that thalidomide was poorly tolerated, and it is unlikely to add
additional antitumor efficacy in this patient population. Our results and those of other groups suggest
that temozolomide is the active agent in this regimen.


## 4. Conclusions

In conclusion, temozolomide offers another option to
consider in the treatment of patients with advanced or metastatic
leiomyosarcoma. Its benefits include the
convenience of oral administration and an improved side-effect profile compared
to traditional chemotherapy regimens for advanced soft tissue sarcoma. Although it does not produce high response
rates, there are a number of patients who have disease stabilization from
months to years even without radiographic responses. There are very few chemotherapy regimens that
offer the possibility of benefit in this patient population, and our data support
the consideration of temozolomide in the treatment of progressive disease. Although several dosing schedules have been
tested in trials (continuous daily dosing, bolus dosing and biweekly dosing),
there is not sufficient evidence to support adopting an alternative dosing
schedule, therefore, we recommend using the 5-day bolus dosing regimen for
temozolomide.Future investigation should focus on determining the
biologic and molecular characteristics of leiomyosarcomas that can predict
response to temozolomide. Methylation of the DNA repair protein
06-methylguanine-DNA-methyltransferase (MGMT) has been identified as a
predictor of response to temozolomide treatment in patients with glioblastoma
multiforme [20]. Epigenetic silencing
of MGMT and/or other key regulatory genes in tumor cells may play a role in
temozolomide resistance, and in the pathogenesis of soft tissue sarcomas. Because of the potential therapeutic benefits
to those patients who may respond to temozolomide, investigation of mechanisms
of response and resistance to this drug warrants further investigation in
leiomyosarcomas.



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*Source: 412503-2008-11-16.xml*