PRIMARY OBJECTIVESthe assessment if survival in grade III glioma without combined 1p/19q loss is improved by - daily temozolomide chemotherapy during radiotherapy - the administration of temozolomide after the end of radiotherapy SECONDARY…
ID
Source
Brief title
Condition
- Nervous system neoplasms malignant and unspecified NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
overall survival as measured from the day of randomization (section 8.2.1.1,
page 38)
Secondary outcome
progression free survival, neurological progression free survival as determined
with the WHO Performance status, cognition as assessed with the Mini Mental
Status Examination (MMSE) and with the use of a short neuropsychological
testbattery, toxicity of temozolomide treatment (chapter 7) and quality of life
assessed with the EORTC QOL C30 questionnaire and the Brain Cancer Module
(chapter 10, chapter 8).
Background summary
Each year about 1000 new glioma are diagnosed in the Netherlands, in about 20%
this concerns a grade III tumor. The median survival of these patients varies
between the 2 and 6 year, depending on prognostic factors. The standard of care
for these patients consists of radiotherapy to involved fields. However,
concomitant and adjuvant chemotherapy with temozolomide plays an increasing
role in the early management of these tumors. Ultimately, the outcome of
patients with this disease is poor, with a fatal outcome being the rule.
Recent research has shown that adjuvant PCV chemotherapy does not improve the
overall survival of newly diagnosed grade III glioma both with and without
combined 1p/19q deletion, although it does improve progression free survival.
These studies have also shown that the presence or absence of combined 1p/19q
deletions is the most important prognostic for survival in thse tumors. The
median survival of patients without combined 1p/19q deletion was shown to be 2
to 3 year, in contrast to 6-7 years for patients with combined 1p/19q loss.
Inother clinical trials is was demonstrated that concurrent and adjuvante
temozolomide chemotherapy improves survival and progression free survival in
grade IV glioma or glioblastoma multiforme. This effect was predominantly
observed in patients with tumors with methylation of the promoter of the MGMT
gen, for which reason these tumors can no longer express alkyltransferase (a
major resistance protein against alkylating andmethylating cytostatic agents
like temozolomide). Because of the design it is not possible to asses which
part of the treatment improves survival: the part with concurent
radio-chemotherapy, the adjuvant part or both. The assessment of this is of
high clinical relevance, as it may shorten treatment considerable.
In view of these studies the questions arises if concurrent and adjuvant
temozolomide chemotherapy also improves survival in grade III glioma
(anaplastic astrocytoma, anaplastic oligoastrocytoma, anaplastic
oligodendroglioma). Because of the large difference in outcome between patients
with and without combined 1p/19q loss different studies will be developed for
these patients. The present study will also assess if a prolongation of
progression free survival has favourable effects onthe functioning of the
patient.
It is expected that this study will determine if combined chemo-irradiation is
also indicated in newly diagnosed grade III glioma without combined 1p/19q
loss. At this moment different these tumors are treated differently in
different institutions, either with or without temozolomide chemotherapy. Both
approaches are currently viewed as the standard of care for these patients. It
is therefore of high clinical interest to determine the impact of the addition
of temozolomide to radiotherapy in this disease.
In this trial the duration of adjuvant treatment has been set on 12 months.
This is clinical practice in many institutions, although others use 6 months.
This duration has also been selected to allow a maximum beneficial impact on
progression free survival.
Study objective
PRIMARY OBJECTIVES
the assessment if survival in grade III glioma without combined 1p/19q loss is
improved by
- daily temozolomide chemotherapy during radiotherapy
- the administration of temozolomide after the end of radiotherapy
SECONDARY OBJECTIVES
in patients with grade III glioma without combined 1p/19q loss
- the determination of the administration of concurrent and adjuvant
temozolomide improves the progression free survival
- the assessment of the safety of concurrent and adjuvant temzolomide in
patients with this tumor, including the assessment of the occurence of delayed
neurotoxic effects
- the assessment of effects on the quality of life of concurrent and adjuvant
temozolomide chemotherapy
(page 17)
Study design
Randomised phase III study with a 2 x2 design, with a randomization between
- radiotherapy with further treatment (which may include temozolomide) at
progression
- radiotherapy with concurrent temozolomide chemotherapy
- radiotherapy with adjuvant temozolomide chemotherapy for 12 months
- radiotherapy with both concurrent and adjuvant temozolomide chemotherapy
(chapter 4, page 20)
Intervention
- All patients will receive radiotherapy on the tumor area to a dosage of 60 gy
in 30 fracties
- For patients randomized to concurrent temozolomide chemotherapy: daily 75
mg/m2 during radiotherapy (including the weekends), with cotrimoxazol for PCP
prophfylaxis
- For patients gerandomized to adjuvant temozolomide chemotherapy: 12 cycles
with 150-200 mg/m2 temozolomide day 1-5 every four weeks.
(chapter 5)
Study burden and risks
The treatment that is investigated in this study is considered standard of care
for patients with glioblastoma multiforme, the most frequent high-grade primary
brain tunmor in adults. Combined chemo-irradation is also increasingly being
used foir the patients with a tumor that is being investigated in the present
study.
The most important side-effects of temozolomide chemotherapy are
myelosuppression with thrombopenia and leukopenia. During concomittant
chemo-radiotherapy with daily temozolomide pneumocystis carinii infections have
been observed, for which reason prophylaxis with cotrimoxazol is indicated.
It is unknown if after prolonged follow-up combined radiotherapy and daily
temozolomide reulsts in anincrease of delayed leukoencephalopathy, with an
increase of cognitive disturbances. This investigation of these disturbances is
one of the objectives of this trial.
The follow-up schedule that is being used in this trial ican be considered as a
standard follow-up schedule for patients with high grade glioma (chapter 6).
Av E Mounier 83/11
Brussel B1200
BE
Av E Mounier 83/11
Brussel B1200
BE
Listed location countries
Age
Inclusion criteria
AT REGISTRATION:;- Histologically confirmed newly diagnosed anaplastic oligodendroglioma, anaplastic oligoastrocytoma or anaplastic astrocytoma by local diagnosis;- Availability of tumor material for central 1p/19q assessment, central MGMT promoter methylation assessment and central pathology review.;- WHO performance status 0-2;- Age >= 18 years;- All patients must use effective contraception if of reproductive potential. Females must not be pregnant or breast feeding;- Absence of known HIV infection, chronic hepatitis B or hepatitis C infection;- Absence of any other serious medical condition that can interfere with follow-up;- Absence of any medical condition which could interfere with oral medication intake (e.g., frequent vomiting, partial bowel obstruction);-Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial;RANDOMIZATION:;The combination of Histologically confirmed newly diagnosed anaplastic oligodendroglioma, anaplastic oligoastrocytoma or anaplastic astrocytoma by local diagnosis AND Absence of combined 1p/19q loss both of which must have been determined by either local testing or central review;- Availability of tumor material for central 1p/19q assessment, central MGMT promoter methylation assessment and central pathology review;- WHO performance status 0-2;- Age >= 18 years;- Previous surgery for a low grade tumor is allowed, provided histological confirmation of an anaplastic tumor is present at the time of progression;- Start of radiotherapy within 8 days from randomization;- Start of radiotherapy within 7 weeks (49 days) from surgery (extra 2 days could be allowed);- Patients must be on a stable or decreasing dose of steroids for at least two weeks;- Adequate hematological, renal and hepatic function;- All patients must use effective contraception if of reproductive potential. Females must not be pregnant or breast feeding;- Absence of known HIV infection, chronic hepatitis B or hepatitis C infection;- Absence of any other serious medical condition that could interfere with follow-up
Exclusion criteria
REGISTRATION:;- Previous other malignancies, except for any previous malignancy which was treated with curative intent more than 5 years prior to registration, and except for adequately controlled limited basal cell carcinoma of the skin, squamous carcinoma of the skin or carcinoma in situ of the cervix.;- Prior chemotherapy (including no treatment with BCNU containing wafers (Gliadel®);- Prior radiotherapy to the brain;RANDOMIZATION:;- Prior chemotherapy (including no treatment with BCNU containing wafers (Gliadel®);- Prior radiotherapy to the brain
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2006-001533-17-NL |
| ClinicalTrials.gov | NCT00626990 |
| CCMO | NL14970.078.07 |