Astrocytoma Clinical Trial
Official title:
A Prospective Cohort to Study the Effect of Postoperative Upfront Temozolomide Chemotherapy on IDH Mutational Low Grade Gliomas in Eloquent Areas
Low grade gliomas (LGGs) are the most common primary central nervous system malignancies.
Brain surgeries with the most possible extent of resection are endeavored to achieve longer
survivals in LGG patients. For patients with tumor located in eloquent areas so that gross
total resection is not applicable, National Comprehensive Cancer Network (NCCN) 2013
guidelines assigned both radiotherapy or chemotherapy as adjuvant treatments of low grade
glioma following surgeries. Retrospective studies have suggested that temozolomide (an oral
chemotherapeutics) chemotherapy have good effects on the control of tumor progression or
recurrence in LGG patients after surgeries, especially in those with isocitrate dehydrogenase
(IDH) gene mutations.
Therefore, our prospective cohort study is to provide a higher level(IIb) of evidence for the
correlation between IDH mutation and the responsiveness to up-front adjuvant metronomic
temozolomide chemotherapy in young patients with LGG located in eloquent brain areas. And
hopefully justify future RCTs with comparison between effects of adjuvant radiotherapy and
chemotherapy in these patients.
Low grade gliomas, according to the 2007 WHO classification of tumors of the central nervous
system, include astrocytomas, oligodendrogliomas, and oligoastrocytomas. It contributes to
25% of diffuse gliomas and 15% of all gliomas in adults. The majority of age group that is
the most vulnerable to this neoplasm is from 30-45 years old. Median survival is usually 5-12
years, but can be prolonged up to 20 years under optimal treatment strategies. National
Comprehensive Cancer Network (NCCN) and Chinese Guideline for Gliomas 2012 both point out
that for LGG patients in low-risk group (oligodendrogliomas or oligoastrocytomas; no more
than 40 years old; KPS 80 and higher; tumor size less than 6cm; no or minor neurological
deficits), "wait and see" strategy could be considered after gross total resection; but when
the tumors are in eloquent areas so that gross total resections are not applicable, the
standard strategies for this specific group of patients are maximum safely resection with
adjuvant treatments (radiotherapy and/or chemotherapy). Conventionally, radiotherapy is used
as adjuvant treatment after surgeries. However, a recent phase III randomized trial comparing
early versus later irradiation has demonstrated that early adjuvant radiotherapy had no
significant impact on overall survival. Moreover, radiotherapy brings as much side effects as
its control of tumor recurrence. It inevitably jeopardizes patients, especially young ones,
with post-radiation cognitive deficits, which impair their social functions. On the other
hand, chemotherapy could be a safer adjuvant treatment for LGG. Several phase II and III
studies demonstrated that single chemotherapy is effective for treating LGG, with 50-75%
response rate (including minor response), and 24-48 months of median duration of response.PCV
regimen (procarbazine-CCNU-vincristine), which is administrated intravenously, used to be
considered standard for LGG (oligodendrogliomas and oligoastrocytomas) chemotherapy, but now
temozolomide (TMZ), an oral alkylating agent, with relatively less side effects than PCV
regimen, is gaining gradual acceptance. Now we propose up-front adjuvant chemotherapy to
achieve the effect of early tumor control as well as avoidance or postponement of adverse
effects caused by premature adjuvant radiotherapy.
As for different schedules of temozolomide, a systematic review suggested an indication that
metronomic regimens of TMZ (75 mg/m2/day for 21 days repeated every 4 weeks) result in better
PFS and response rate when compared to the conventional standard 5 day regimen (200 mg/m2/day
for 5 days, repeated every 4 weeks), despite of insufficient available data and study
heterogeneity, thus justifying future well designed trials to verify the efficacy of the
metronomic regimen. More frequent administration of TMZ will lead to MGMT (O6-methylguanine
DNA methyl transferase) depletion and render higher levels of O6-methylated DNA adducts, thus
reducing the chemotherapeutic resistance.
The spontaneous behavior of LGGs, as well as their response to therapy, is difficult to
predict, and their outcome is highly variable. These clinical features are closely relevant
to their genetic characteristics, including IDH (isocitrate dehydrogenase) gene, with 2
subtypes, IDH1 and IDH2 (less common). These genetic mutations occur in more than 70% primary
LGGs. And its prognostic significance of gliomas has been reported in the New England Journal
of Medicine, Journal of Clinical Oncology, and Neuro-oncology. A retrospective study
suggested its predictive value of high LGGs sensitivity to TMZ. Basic research provided us
the rationale that overexpression of wild IDH1 gene resulted in chemotherapy resistance to a
high dose of TMZ in vivo and in vitro, while IDH1 mutation caused cell cycle arrest in G1
stage, with a compromised ability of proliferation and invasion, raising sensitivity to
chemotherapy.
During our previous clinical practice, it is interesting to reveal the consistence of IDH
mutation, MGMT methylation and 1p19q co-deletion in WHO Grade II and Grade III gliomas. It
theoretically acknowledged potential higher sensitivity of TMZ chemotherapy in LGGs.
In order to verify the predictive significance of IDH mutation for a higher sensitivity of
LGGs in eloquent areas which entail gross total resection inapplicable, higher level of
evidence should be provided. And recent RANO (response assessment in neuro-oncology) revised
guidelines for evaluations of objective response rate, cognitive functions, and quality of
life have better facilitated standard trials.
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