Activity Of Irinotecan Plus Temozolomide For Different Molecular Pathologic Types Of Recurrent Glioblastomas

Background and objectives Glioblastoma is the most common malignant glioma in adults.It makes up about 80% of all malignant brain tumors.Glioblastoma is categotized as grade ? glioma according to the WHO pathologic classification.Glioblastoma has a peak incidence in adults older than 40 years of age.According to the statistics,with 2-3 cases are diagnosed as glioblastoma per 100,000 people per annum in China.Local tissue invasiveness,neoangiogenesis,intratumor heterogeneity and other tumor characteristics are among the most important hallmarks of the aggressiveness of glioblastoma.Since 2008,the Cancer Genome Atlas(TCGA)Research Network has generated a comprehensive catalog of genomic abnormalities driving tumorigenesis.Based on this mutational spectrum,glioblastoma can be further categorized into four main subtypes: classical type,mesenchymal type,proneural type and neural type.Although continued in-depth studies have been conducted,glioblastoma patients still have a poor prognosis.This is due to glioblastoma being highly aggressive,chemoresistant and radioresistant,thereby rarely achieving complete cure.The median survival time is only about 14-16 months,and the 2-year survival rate is around 30%.The current standard treatment of globlastoma by Stupp et al.established in 2005 involves the maximal safe surgical resection,concomitant administration of temozolomide with fractionated radiotherapy,with subsequent adjuvant temozolomide for more than 6 cycles.Due to the absence of a definite line of demarcation between the tumor and normal brain parenchyma,complete surgical resection is rarely possible even after the current standard therapy.The residual tumor initiating cells(TICs)that infiltrate the surrounding brain tissue can easily replicate the tumor and often become more aggressive,with a higher malignant potential therefore requiring more aggressive treatment and making the prognosis worse.Six months progress free survival rate is only 5%-15%.With further study in the field of molecular pathology of the central nervous system the 2016 World Health Organization(WHO)Classification Visson 4 of Tumors of the Central nervous system was established in 2016.Recently,a large number of molecular genetics details in glioma were added which helped in the further clssification and diagnosis.Patients with the same histopathologial gliomas may have different prognoses as the above classification divides the same glioma into lesions with different genetic molecular content.There are a series of glioma related biomolecular markers that have been discovered,such as IDH gene mutation,MGMT promoter metylation,chromosome 1p/19 q deletion,EGFR mutations etc.These provide a valuable information regarding clinical treatment.However,as for different molecular pathological types of recurrent glioblastoma,the clinical efficacy of classical chemotherapy regimen has not been adequately reported.Irinotecan(CPT-11)is a camptothecin derivative,which is a topoismerase ? inhibitor,incativating tumor cells by interfering with RNA transcription and DNA replication.The predominant excretion route is feces(64%)followed by urine(32%).Irinotecan has been first approved for treatment of metastatic CRC either alone or in combination with 5-Fu and other relevant drugs.It has shown activity in esophageal cancer,gastric cancer,lung cancer,leukemia,lymphoma,cervical cancer,breast cancer and other solid tumors.The main dose limiting toxicities are neutropenia and late onset diarrhea.Temozolomide is an alkylating agent with antitumor activity,which when administered is converted into the active compound MITC(5-(3-methyltriazen-1-yl)imidazole-4-amide)by non-enzymatic pathway.The cytotoxicity is mainly due to the transfer of methyl groups at the position of guanine O6,which produces O6-methylguanine in DNA replication,activating DNA mismatch repair system.The persistent presence of methyl groups on guanin destruct the DNA double helix structure causing cell cycle arrest leading to cell death.Temozolomide has a high bioavailability in central nervous system tumors.MGMT,which is synthesized by tumor cells,can remove the methyl group of O6 guanine site from temozolomide synthesis.Therefore,the high-level expression of MGMT protein is the main mechanism for temozolomide resistance.Both Irinotecan and temozolomide can pass the blood-brain barrier.The study confirmed that the two drugs can have a good combined curative effect.China Central Nevous System Disease and Treatment Guidelines recommend this therapeutic regimen as the stanard treatment for patients with recurrent glioblastoma.This study analyzed the clinical data of recurrent glioblastoma patients,who have been treated with irinotecan combined with temozolomide chemotherapy in the past two years,and disscussed the clinical efficacy of this regimen in different molecular pathologic types of recurrent glioblastoma.Methods A total of 48 patients with recurrent glioblastoma from July 2014 to December 2016 in the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed in this study.All the patients had undergone surgery,radiotherapy,synchronized temozolomide chemotherapy and adjuvant temozolomide 4-6 cycle standard regimen.After imageology confirmed tumor recurrence,patients received temozolomide 150-200mg/(?·d),from the 1st day to 5th days.As for irinotecan 60mg/(?·d)was given on the 1st day and the 8th day,28 days is one course.Review head MRI were down every 2 weeks to evaluate the efficacy of the treatment.According to whether there was mutation in IDH,and whether MGMT was methylated the patients were divided into different groups.Then the response rate,progress free survival,overall survival time,and the occurrence of adverse reactions were analyzed.SPSS 18.0 statistic software was used to process and analyze data.The count data were compared by chi-square test,the progression free and overall survival rates were calculated by the Kaplan-Meier method and the log-rank test was used to analyze the significance of differences in survival.A P value<0.05 was considered statistically significant.Results 1.48 patients received irinotecan combined with temozolomide chemotherapy for 4-6 cycles.According to the follow-up data statistics,2 cases of complete response(4.2%),17 cases of partial response(35.4%),15 cases of stable disease(31.3%)and 14 cases of progressive disease(29.1%)were recorded.The response rate was 70.9%.It was considered that irinotecan combined with temozolomide was an effective treatment for recurrent glioblastoma.2.The data of 48 patients with recurrent glioblastoma was completed.Subgroup analysis showed that 0 cases of complete response(0),9 cases of partial response(30.0%),9 cases of stable disease(30.0%)and 12 cases of progressive disease(40.0%)in 30 patients with IDH wild type group.The disease control rate was 60%.There were 2 cases of complete response(11.1%),8 cases of partial response(44.5%),6 cases of stable disease(33.3%)and 2 cases of progressive disease(11.1%).The disease control rate was 88.9% in 18 patients with IDH mutant.The disease control rate of IDH mutant group was higher than that of IDH wild type group(P<0.05).In the other MGMT unmethylated group,including 23 patients,there were 0 cases of complete response(0),7 cases of partial response(30.4%),6 cases of stable disease(26.1%)and 10 cases of progressive disease(43.5%).The disease control rate was 56.5%.In the last 25 patients with MGMT methylation,2 cases of complete response(4.2%),10 cases of partial response(40.0%),9 cases of stable disease(36.0%)and 4 cases of progressive disease(16.0%).The disease control rate was 84%.The disease control rate of MGMT methylated group was higher than that of MGMT unmethylated group,the difference was statistically significant(P<0.05).3.According to the molecular pathology,the results showed that at the PFS of IDH wild type group was 5.48 months(95%CI:4.642-6.311),and the 2,6-month PFS were 86.7% and 36.7%,OS was 11.30 months(95%CI:9.046-13.554).IDH mutant group PFS was 6.79 months(95%CI:5.725-7.863),2,6-months PFS were 94.4% and 55.6%,OS was 17.33 months(95%CI:14.177-20.489).PFS and OS of IDH mutant group and NOS group were superior to those of IDH wild type group(P<0.05).The PFS of MGMT unmethylation group was 5.04 months(95%CI:4.109-5.978),and the 2,6-month PFS were 83.6% and 30.4%,OS was 10.17 months(95%CI:8.381-11.967).MGMT methylation group PFS was 6.82 months(95%CI :5.964-7.684),2,6-months PFS were 96% and 56%,OS was 16.68 months(95%CI:13.675-19.685).The PFS of MGMT methylation group was significantly higher than that of wild type group(P<0.05).The OS was also superior to MGMT unmethylated group and the difference was statistically significant(P<0.05).4.The 48 patients had different degrees of hematological toxicity,gastrointestinal reactions fatigue and other adverse reactions.Hematologic toxicity was mainly reflected in the leukocyte and thrombocyte,gastrointestinal reactions mainly manifested as nausea,vomiting and diarrhea,among which,most had ?-? adverse reactions.In the IDH wild type group and the IDH mutant group or the MGMT unmethylation group and the MGMT methylation group,subgroup analysis was performed respectively.There was no significant difference in the incidence of adverse reactions between the subgroups(P>0.05).Conclusion 1.In the patients with recurrent glioblastoma treated with irinotecan combined with temozolomide chemotherapy.2.According to the molecular pathologic type,the clinical efficacy and prognosis of IDH mutant type was superior to the IDH wild.3.Molecular pathology detection of MGMT methylated patients with clinical efficacy and prognosis was better than MGMT unmethylated patients.