<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02209428</url>
  </required_header>
  <id_info>
    <org_study_id>KY2014-182</org_study_id>
    <nct_id>NCT02209428</nct_id>
  </id_info>
  <brief_title>A Prospective Cohort to Study the Effect of Temozolomide on IDH Mutational Low Grade Gliomas</brief_title>
  <official_title>A Prospective Cohort to Study the Effect of Postoperative Upfront Temozolomide Chemotherapy on IDH Mutational Low Grade Gliomas in Eloquent Areas</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Huashan Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Huashan Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Low grade gliomas (LGGs) are the most common primary central nervous system malignancies.&#xD;
      Brain surgeries with the most possible extent of resection are endeavored to achieve longer&#xD;
      survivals in LGG patients. For patients with tumor located in eloquent areas so that gross&#xD;
      total resection is not applicable, National Comprehensive Cancer Network (NCCN) 2013&#xD;
      guidelines assigned both radiotherapy or chemotherapy as adjuvant treatments of low grade&#xD;
      glioma following surgeries. Retrospective studies have suggested that temozolomide (an oral&#xD;
      chemotherapeutics) chemotherapy have good effects on the control of tumor progression or&#xD;
      recurrence in LGG patients after surgeries, especially in those with isocitrate dehydrogenase&#xD;
      (IDH) gene mutations.&#xD;
&#xD;
      Therefore, our prospective cohort study is to provide a higher level(IIb) of evidence for the&#xD;
      correlation between IDH mutation and the responsiveness to up-front adjuvant metronomic&#xD;
      temozolomide chemotherapy in young patients with LGG located in eloquent brain areas. And&#xD;
      hopefully justify future RCTs with comparison between effects of adjuvant radiotherapy and&#xD;
      chemotherapy in these patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Low grade gliomas, according to the 2007 WHO classification of tumors of the central nervous&#xD;
      system, include astrocytomas, oligodendrogliomas, and oligoastrocytomas. It contributes to&#xD;
      25% of diffuse gliomas and 15% of all gliomas in adults. The majority of age group that is&#xD;
      the most vulnerable to this neoplasm is from 30-45 years old. Median survival is usually 5-12&#xD;
      years, but can be prolonged up to 20 years under optimal treatment strategies. National&#xD;
      Comprehensive Cancer Network (NCCN) and Chinese Guideline for Gliomas 2012 both point out&#xD;
      that for LGG patients in low-risk group (oligodendrogliomas or oligoastrocytomas; no more&#xD;
      than 40 years old; KPS 80 and higher; tumor size less than 6cm; no or minor neurological&#xD;
      deficits), &quot;wait and see&quot; strategy could be considered after gross total resection; but when&#xD;
      the tumors are in eloquent areas so that gross total resections are not applicable, the&#xD;
      standard strategies for this specific group of patients are maximum safely resection with&#xD;
      adjuvant treatments (radiotherapy and/or chemotherapy). Conventionally, radiotherapy is used&#xD;
      as adjuvant treatment after surgeries. However, a recent phase III randomized trial comparing&#xD;
      early versus later irradiation has demonstrated that early adjuvant radiotherapy had no&#xD;
      significant impact on overall survival. Moreover, radiotherapy brings as much side effects as&#xD;
      its control of tumor recurrence. It inevitably jeopardizes patients, especially young ones,&#xD;
      with post-radiation cognitive deficits, which impair their social functions. On the other&#xD;
      hand, chemotherapy could be a safer adjuvant treatment for LGG. Several phase II and III&#xD;
      studies demonstrated that single chemotherapy is effective for treating LGG, with 50-75%&#xD;
      response rate (including minor response), and 24-48 months of median duration of response.PCV&#xD;
      regimen (procarbazine-CCNU-vincristine), which is administrated intravenously, used to be&#xD;
      considered standard for LGG (oligodendrogliomas and oligoastrocytomas) chemotherapy, but now&#xD;
      temozolomide (TMZ), an oral alkylating agent, with relatively less side effects than PCV&#xD;
      regimen, is gaining gradual acceptance. Now we propose up-front adjuvant chemotherapy to&#xD;
      achieve the effect of early tumor control as well as avoidance or postponement of adverse&#xD;
      effects caused by premature adjuvant radiotherapy.&#xD;
&#xD;
      As for different schedules of temozolomide, a systematic review suggested an indication that&#xD;
      metronomic regimens of TMZ (75 mg/m2/day for 21 days repeated every 4 weeks) result in better&#xD;
      PFS and response rate when compared to the conventional standard 5 day regimen (200 mg/m2/day&#xD;
      for 5 days, repeated every 4 weeks), despite of insufficient available data and study&#xD;
      heterogeneity, thus justifying future well designed trials to verify the efficacy of the&#xD;
      metronomic regimen. More frequent administration of TMZ will lead to MGMT (O6-methylguanine&#xD;
      DNA methyl transferase) depletion and render higher levels of O6-methylated DNA adducts, thus&#xD;
      reducing the chemotherapeutic resistance.&#xD;
&#xD;
      The spontaneous behavior of LGGs, as well as their response to therapy, is difficult to&#xD;
      predict, and their outcome is highly variable. These clinical features are closely relevant&#xD;
      to their genetic characteristics, including IDH (isocitrate dehydrogenase) gene, with 2&#xD;
      subtypes, IDH1 and IDH2 (less common). These genetic mutations occur in more than 70% primary&#xD;
      LGGs. And its prognostic significance of gliomas has been reported in the New England Journal&#xD;
      of Medicine, Journal of Clinical Oncology, and Neuro-oncology. A retrospective study&#xD;
      suggested its predictive value of high LGGs sensitivity to TMZ. Basic research provided us&#xD;
      the rationale that overexpression of wild IDH1 gene resulted in chemotherapy resistance to a&#xD;
      high dose of TMZ in vivo and in vitro, while IDH1 mutation caused cell cycle arrest in G1&#xD;
      stage, with a compromised ability of proliferation and invasion, raising sensitivity to&#xD;
      chemotherapy.&#xD;
&#xD;
      During our previous clinical practice, it is interesting to reveal the consistence of IDH&#xD;
      mutation, MGMT methylation and 1p19q co-deletion in WHO Grade II and Grade III gliomas. It&#xD;
      theoretically acknowledged potential higher sensitivity of TMZ chemotherapy in LGGs.&#xD;
&#xD;
      In order to verify the predictive significance of IDH mutation for a higher sensitivity of&#xD;
      LGGs in eloquent areas which entail gross total resection inapplicable, higher level of&#xD;
      evidence should be provided. And recent RANO (response assessment in neuro-oncology) revised&#xD;
      guidelines for evaluations of objective response rate, cognitive functions, and quality of&#xD;
      life have better facilitated standard trials.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date>June 2014</start_date>
  <completion_date type="Anticipated">May 2019</completion_date>
  <primary_completion_date type="Anticipated">April 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Objective Response Rate, ORR</measure>
    <time_frame>Within 72 hours after surgery, at the beginning of chemotherapy, every 2 months thereafter up to a year, every 3-6 months after a year, until the first documented progression or date of death from any cause, whichever came first, up to 2 years.</time_frame>
    <description>According to the revised RANO criteria (M J van den Bent, et al. 2011), compared to residual tumor volume calculated with iMRI T2/Flair right after surgery and before up-front adjuvant chemotherapy (Baseline tumor volume):&#xD;
Complete response (CR): disappearance of abnormality Partial response (PR): no less than 50% reduction Minimal response (MR): no less than 25% but less than 50% reduction Stable disease (SD): less than 25% reduction also less than 25% increase Progressive disease (PD): no less than 25% increase&#xD;
Enhanced T1-weighted imaging, magnetic resonance spectroscopy (MRS), Diffusion tensor imaging (DTI) and perfusion-weighted imaging (PWI) will also be utilized to detect progressions.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Velocity of Diameter Evolution, VDE</measure>
    <time_frame>Within 72 hours after surgery, at the beginning of chemotherapy, every 2 months thereafter up to a year, every 3-6 months after a year, until the first documented progression or date of death from any cause, whichever came first, up to 2 years.</time_frame>
    <description>According to the Definition of New Endpoints by E. Mandonnet et al, 2013, VDE is calculated with formula D = (2 × V)^1/3, (V= tumor volume).&#xD;
Uncontrolled: unchanged or increased VDE compared to baseline VDE. Slowed down: decreased VDE compared to baseline VDE, but still positive. Stabilized: VDE is close to 0 mm/year. Reversed: negative VDE. Treatment escape and relapse: re-growth of the tumor greater than 2 mm, during the course of chemotherapy and after the end of chemotherapy, respectively.&#xD;
Intensity of response (IOR): how much the diameter has been reduced by the therapy.&#xD;
Duration of response (DOR): the time period between treatment onset and treatment escape or relapse. If Replapse (25% increase/VDE&gt;2mm/Maligmant enhancement), start 2° treatment: Second surgery or radiotherapy or salvage chemotherapy</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression free survival (PFS)-6, -12, -24</measure>
    <time_frame>6, 12 and 24 months after the 1st cycle of chemotherapy</time_frame>
    <description>The survival rate of followed patients without progressive disease (PD) 6, 12, and 24 months after the 1st cycle of chemotherapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognitive functions</measure>
    <time_frame>At the beginning of chemotherapy, every 2 months thereafter up to a year, and every 3-6 months after a year of follow-up, until the first documented (malignant) progression or date of death from any cause, whichever came first, up to 2 years.</time_frame>
    <description>Test battery:&#xD;
Measured with Minimal Mental State Examination (MMSE); Hopkins verbal learning test-revised; Trail making test, part A and B; Multilingual aphasia examination controlled oral word association</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life (QoL)</measure>
    <time_frame>At the beginnning of chemotherapy, every 2 months thereafter up to a year, and every 3-6 months after a year of follow-up, until the first documented (malignant) progression or date of death from any cause, whichever came first, up to 2 years.</time_frame>
    <description>Measured with EORTC QLQ-C30 and EORTC-BN20. Duration of response with good quality of life is defined as Time with good quality of life (TQL).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse effect of chemotherapy</measure>
    <time_frame>At the beginning of chemotherapy, every 2 months thereafter up to a year, until the first documented (malignant) progression or date of death from any cause, whichever came first, up to 2 years.</time_frame>
    <description>Blood routine and kidney/liver functions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Malignant progression-free survival (MPFS) -6, -12, -24</measure>
    <time_frame>6, 12 and 24 months after the 1st cycle of chemotherapy</time_frame>
    <description>The survival rate of followed patients without any MRI T1 enhancing signals in 6, 12, and 24 months after the 1st cycle of chemotherapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Symptom Burden</measure>
    <time_frame>At the beginning of the chemotherapy, every 2 months thereafter up to a year, then every 3 months up to 2 years</time_frame>
    <description>Measured with M.D. Anderson Symptom Inventory Brain Tumor Module, MDASI-BT.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Seizure activity</measure>
    <time_frame>At the beginning of the chemotherapy, every 2 months thereafter up to a year, then every 3 months up to 2 years</time_frame>
    <description>Measured by one neurologist, number and type of seizure and medication in the past month before each follow-up visit are recorded.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">54</enrollment>
  <condition>Astrocytoma</condition>
  <condition>Oligodendroglioma</condition>
  <condition>Oligoastrocytoma</condition>
  <arm_group>
    <arm_group_label>IDH wild type</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients with IDH wild type, according to the result of genetic sequencing of their surgical resected specimens. Intervention: oral temozolomide, 75 mg/m2/day for 21 days repeated every 4 weeks, 6 cycles.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>IDH mutation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients with IDH mutations, according to the result of genetic sequencing of their surgical resected specimens. Intervention: oral temozolomide, 75 mg/m2/day for 21 days repeated every 4 weeks, 6 cycles.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Temozolomide</intervention_name>
    <description>75 mg/m2/day for 21 days repeated every 4 weeks, 6 cycles.</description>
    <arm_group_label>IDH mutation</arm_group_label>
    <arm_group_label>IDH wild type</arm_group_label>
    <other_name>Temodar</other_name>
    <other_name>Temodal</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  18 years &lt; age ≤ 40 years, both genders.&#xD;
&#xD;
          -  No neurologic cognitive deficits (MMSE ≥ 27), no psychiatric abnormalities before&#xD;
             surgery, pre-operative KPS ≥ 80.&#xD;
&#xD;
          -  Tumors located in eloquent areas or deeply located nuclei, rendering radiological&#xD;
             complete resection inapplicable, according to updated standards of extent of&#xD;
             resection: as for non-enhancing LGG, postoperative MRI within 72h shows absence of any&#xD;
             preoperative T2/FLAIR signal changes - complete resection; and for enhancing LGG,&#xD;
             postoperative MRI shows total removal of preoperative enhancing tissue - complete&#xD;
             resection of enhancing tumor; and total removal of enhancing and non-enhancing tissues&#xD;
             (T2/FLAIR) - complete resection of detectable tumor.&#xD;
&#xD;
          -  Post-operative histological pathology confirms LGGs (astrocytomas, oligodendrogliomas,&#xD;
             or oligoastrocytomas, 2007 WHO classification Grade II).&#xD;
&#xD;
          -  No contraindications to TMZ chemotherapy.&#xD;
&#xD;
          -  Informed consent to TMZ chemotherapy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Tumor involves more than 3 cerebral lobes (gliomatosis or multiple gliomas).&#xD;
&#xD;
          -  Tumor is complicated with other intracranial neoplasms (e.g. metastatic tumors or&#xD;
             meningiomas).&#xD;
&#xD;
          -  Tumor is complicated with systematic malignancies.&#xD;
&#xD;
          -  Dysfunctions of other vital organs: liver and kidney (ALT﹥40U/L, AST &gt; 40U/L,&#xD;
             creatinine &gt; 97-106μmol/L, urea nitrogen &gt; 7.1mmol/L, or other lab abnormalities);&#xD;
             Heart (NYHA II-IV); Lungs (hypoxemia).&#xD;
&#xD;
          -  Physiological pregnancy.&#xD;
&#xD;
          -  Participate in other clinical trials at meantime.&#xD;
&#xD;
          -  History of severe anaphylaxis.&#xD;
&#xD;
          -  Voluntarily quit or decline chemotherapy.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jinsong Wu, Professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Huashan Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Huashan Hospital Affiliated to Fudan University</name>
      <address>
        <city>Shanghai</city>
        <state>Shanghai</state>
        <zip>200040</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
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    <citation>van den Bent MJ, Taphoorn MJ, Brandes AA, Menten J, Stupp R, Frenay M, Chinot O, Kros JM, van der Rijt CC, Vecht ChJ, Allgeier A, Gorlia T; European Organization for Research and Treatment of Cancer Brain Tumor Group. Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971. J Clin Oncol. 2003 Jul 1;21(13):2525-8. doi: 10.1200/JCO.2003.12.015.</citation>
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    <citation>Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009 Feb 19;360(8):765-73. doi: 10.1056/NEJMoa0808710.</citation>
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    <citation>E. Mandonnet et al. Toward the Definition of New Endpoints. H. Duffau (ed.), Diffuse Low-Grade Gliomas in Adults, DOI 10.1007/978-1-4471-2213-5_29, Springer-Verlag London 2013</citation>
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    <citation>van den Bent MJ, Afra D, de Witte O, Ben Hassel M, Schraub S, Hoang-Xuan K, Malmstrom PO, Collette L, Pierart M, Mirimanoff R, Karim AB; EORTC Radiotherapy and Brain Tumor Groups and the UK Medical Research Council. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet. 2005 Sep 17-23;366(9490):985-90. doi: 10.1016/S0140-6736(05)67070-5. Erratum In: Lancet. 2006 Jun 3;367(9525):1818.</citation>
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  <verification_date>February 2019</verification_date>
  <study_first_submitted>July 30, 2014</study_first_submitted>
  <study_first_submitted_qc>August 3, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 5, 2014</study_first_posted>
  <last_update_submitted>February 20, 2019</last_update_submitted>
  <last_update_submitted_qc>February 20, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 21, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Huashan Hospital</investigator_affiliation>
    <investigator_full_name>Jinsong Wu</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Temozolomide</keyword>
  <keyword>IDH mutation</keyword>
  <keyword>Low grade glioma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glioma</mesh_term>
    <mesh_term>Astrocytoma</mesh_term>
    <mesh_term>Oligodendroglioma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Temozolomide</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02209428
org study id: KY2014-182
nct id: NCT02209428
lead sponsor: 
has dmc: Yes
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.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Outcomes Assessor)
measure: Objective Response Rate, ORR
time frame: Within 72 hours after surgery, at the beginning of chemotherapy, every 2 months thereafter up to a year, every 3-6 months after a year, until the first documented progression or date of death from any cause, whichever came first, up to 2 years.
description: According to the revised RANO criteria (M J van den Bent, et al. 2011), compared to residual tumor volume calculated with iMRI T2/Flair right after surgery and before up-front adjuvant chemotherapy (Baseline tumor volume):
Complete response (CR): disappearance of abnormality Partial response (PR): no less than 50% reduction Minimal response (MR): no less than 25% but less than 50% reduction Stable disease (SD): less than 25% reduction also less than 25% increase Progressive disease (PD): no less than 25% increase
Enhanced T1-weighted imaging, magnetic resonance spectroscopy (MRS), Diffusion tensor imaging (DTI) and perfusion-weighted imaging (PWI) will also be utilized to detect progressions.
measure: Velocity of Diameter Evolution, VDE
time frame: Within 72 hours after surgery, at the beginning of chemotherapy, every 2 months thereafter up to a year, every 3-6 months after a year, until the first documented progression or date of death from any cause, whichever came first, up to 2 years.
description: According to the Definition of New Endpoints by E. Mandonnet et al, 2013, VDE is calculated with formula D = (2 × V)^1/3, (V= tumor volume).
Uncontrolled: unchanged or increased VDE compared to baseline VDE. Slowed down: decreased VDE compared to baseline VDE, but still positive. Stabilized: VDE is close to 0 mm/year. Reversed: negative VDE. Treatment escape and relapse: re-growth of the tumor greater than 2 mm, during the course of chemotherapy and after the end of chemotherapy, respectively.
Intensity of response (IOR): how much the diameter has been reduced by the therapy.
Duration of response (DOR): the time period between treatment onset and treatment escape or relapse. If Replapse (25% increase/VDE>2mm/Maligmant enhancement), start 2° treatment: Second surgery or radiotherapy or salvage chemotherapy
measure: Progression free survival (PFS)-6, -12, -24
time frame: 6, 12 and 24 months after the 1st cycle of chemotherapy
description: The survival rate of followed patients without progressive disease (PD) 6, 12, and 24 months after the 1st cycle of chemotherapy
measure: Cognitive functions
time frame: At the beginning of chemotherapy, every 2 months thereafter up to a year, and every 3-6 months after a year of follow-up, until the first documented (malignant) progression or date of death from any cause, whichever came first, up to 2 years.
description: Test battery:
Measured with Minimal Mental State Examination (MMSE); Hopkins verbal learning test-revised; Trail making test, part A and B; Multilingual aphasia examination controlled oral word association
measure: Quality of life (QoL)
time frame: At the beginnning of chemotherapy, every 2 months thereafter up to a year, and every 3-6 months after a year of follow-up, until the first documented (malignant) progression or date of death from any cause, whichever came first, up to 2 years.
description: Measured with EORTC QLQ-C30 and EORTC-BN20. Duration of response with good quality of life is defined as Time with good quality of life (TQL).
measure: Adverse effect of chemotherapy
time frame: At the beginning of chemotherapy, every 2 months thereafter up to a year, until the first documented (malignant) progression or date of death from any cause, whichever came first, up to 2 years.
description: Blood routine and kidney/liver functions
measure: Malignant progression-free survival (MPFS) -6, -12, -24
time frame: 6, 12 and 24 months after the 1st cycle of chemotherapy
description: The survival rate of followed patients without any MRI T1 enhancing signals in 6, 12, and 24 months after the 1st cycle of chemotherapy
measure: Symptom Burden
time frame: At the beginning of the chemotherapy, every 2 months thereafter up to a year, then every 3 months up to 2 years
description: Measured with M.D. Anderson Symptom Inventory Brain Tumor Module, MDASI-BT.
measure: Seizure activity
time frame: At the beginning of the chemotherapy, every 2 months thereafter up to a year, then every 3 months up to 2 years
description: Measured by one neurologist, number and type of seizure and medication in the past month before each follow-up visit are recorded.
arm group label: IDH wild type
arm group type: Active Comparator
description: Patients with IDH wild type, according to the result of genetic sequencing of their surgical resected specimens. Intervention: oral temozolomide, 75 mg/m2/day for 21 days repeated every 4 weeks, 6 cycles.
arm group label: IDH mutation
arm group type: Experimental
description: Patients with IDH mutations, according to the result of genetic sequencing of their surgical resected specimens. Intervention: oral temozolomide, 75 mg/m2/day for 21 days repeated every 4 weeks, 6 cycles.
intervention type: Drug
intervention name: Temozolomide
description: 75 mg/m2/day for 21 days repeated every 4 weeks, 6 cycles.
arm group label: IDH mutation
arm group label: IDH wild type
other name: Temodar
other name: Temodal
criteria: 
gender: All
minimum age: 18 Years
maximum age: 40 Years
healthy volunteers: No
last name: Jinsong Wu, Professor
role: Principal Investigator
affiliation: Huashan Hospital
facility: 
country: China
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responsible party type: Principal Investigator
investigator affiliation: Huashan Hospital
investigator full name: Jinsong Wu
investigator title: Professor
mesh term: Glioma
mesh term: Astrocytoma
mesh term: Oligodendroglioma
mesh term: Temozolomide