Treatment And Prognosis Of High-Grade Gliomas: Temozolomide Vs. Standard PCV

Cancer is an unforgiving disease that can ravage the human body and one of the most abysmal forms includes: brain cancer. Tumors of the brain can be classified as either primary or secondary, where primary brain tumors originate in the brain and secondary tumors develop elsewhere in the body and eventually metastasize to the brain. Primary brain tumors — also known as gliomas — develop from the glial cells of both the central nervous system (CNS) that provide the insulation and support for the function of neurons in the body. These gliomas are further classified into four grades. Grades I and II are low grade gliomas (LGG) and grades III and IV are considered high grade gliomas (HGG). Gliomas account for 29%-35% of CNS tumors that present in adolescents and young adults aged, 15-19 years, with around two thirds being low grade and the remaining being high grade. In addition, childhood gliomas most often also present as LGG with HGG accounting for only 8-12% of primary CNS tumors; however, low prevalence also accompanies bleak long-term survival rates of only around 10% children.

This literature review will be focused on primary brain tumors, specifically high-grade gliomas. These tumors invade normal brain tissue and create excess pressure that impacts various cognitive capabilities leading to symptoms such as headaches and speech problems to memory loss and personality changes. Since there are not absolute panaceas for most high-grade gliomas, many treatments seek to relieve symptoms and even eliminate or control the tumor itself by turning to surgery, radiation, or chemotherapy. The two main treatments that will be the focus of this literature review will be two common forms of chemotherapy treatment, Temozolomide (TMZ) and a combination of Procarbazine, Lomustine (CCNU), and Vincristine, commonly known as PCV. Temozolomide is an anti-cancer chemotherapy drug and is classified as an “alkylating agent”, which means it adds an alkyl group to DNA molecules of cells leading to improper double helix formation. It’s given orally as a capsule and used more often as the modern standard of chemotherapy as it has a higher tolerability amongst and decreased hematologic toxicity amongst patients. This drug works by disrupting the abnormal cell cycle that tumors have corrupted normal cells into adopting. Cancerous cells no longer have the normal cell cycle checkpoints that place a limit on division, thus, temozolomide acts as a cell cycle disrupter by damaging the RNA or DNA of the cell to prevent division; with no division, cells become unviable and die — sometimes even committing cell suicide — causing the tumor to eventually shrink. PCV is a similar anti-cancer chemotherapy drug but is consisted of 3 component drugs that are very similar but differ in a few ways. Procarbazine and Lomustine, like Temozolomide, are considered “alkylating agents”. They are also both administered orally by capsule and work to destroy the RNA or DNA within the cancerous cells of the patient in order to reduce the size of the tumor. On the other hand, Vincristine is not an alkylating agent and is not administered orally by capsule, but instead given through intravenous injection or infusion — it also works to destroy the RNA or DNA within cancerous cells in order to induce tumor reduction.

In this study, researchers conducted a comparison of PCV with two Temozolomide schedules (standard 5-day 200 mg/m2/day schedule and a 21-day mg/m2/day schedule) by measuring the biomarker, O6-methylguanine-DNA methyltransferase (MGMT) gene. This gene can be used as a molecule marker for the previously mentioned anti-cancer alkylating agent chemotherapy drugs. Decreased expression of the protein product from the methylation of the MGMT promoter is believed to compromise the repair of DNA damage caused by the alkylating agents, thus leading to subsequent cell death. In addition to MGMT methylation status, an IDH1 or IDH2 mutation were also used as important biomarkers to assess the efficacy of both drugs in patients with high-grade gliomas. The objective of this research was to evaluate the prognostic and predictive value of a range of molecular changes for adult brain tumors in response to TMZ over PCV. Their hypothesis entailed a higher intensity treatment of temozolomide to induce a response in the presence of one or more unmethylated copies of the MGMT gene. The study was supported by Cancer Research UK and utilized an open-label, randomized control trial where participants were drawn from 447 patients with recurrent high-grade gliomas. Inclusion criteria for these patients were that they had to be “chemo-naïve adults of either sex with histologically verified AA, GB, AOA or GS (WHO grade III/IV at diagnosis, relapse or transformation) who had undergone primary treatment including radiotherapy completed >2 months before randomization, had evidence of progression confirmed by evaluable enhancing recurrent tumor on contrast enhanced MRI/CT within the 2 weeks prior to start of treatment, and were considered fit for chemotherapy. ” Tumor tissue samples were extracted from the patients upon the first diagnosis of a high-grade tumor and was utilized for DNA isolation and analysis; additional mutation analysis of IDH1, IDH2, tumor protein 53 (TP53), and MGMT methylation analysis was also conducted on tissue samples. The statistical tests utilized within this study included, chai-squared test of association and chai-squared test of heterogeneity, as well as a t-test to compare the mean age across different types of abnormalities. The primary outcome is the measure for the assessment of prognostic and predictive markers, which was survival. Survival was calculated from the date of induction “into the main trial to the date of death, or last known to be alive. ”

LOE Of the 447 patients who participated in the study, only 309 patients were eligible cases regarding the tissue samples received. However, of those 309 cases, to conduct a central pathology review and molecular analysis for MGMT methylation and IDH1/2 mutation analysis was only plausible in 281 and 282 cases, respectively — exon analysis of TP53 was only successful in 82 cases. P-value of IDH1 mutation was p < 0. 001 indicating significant results and that individually — amongst several other biomarkers tested such as chromosome 7 and 10, EGFR amplification, and PTEN deletion — an IDH1 mutation was associated with better prognosis for survival. MGMT methylation proved to not be statistically significant (p value > 0. 1) in reporting whether TMZ proved to be a greater benefit over PCV. Researchers concluded that MGMT methylation and IDH1/2 mutation were found to be independent prognostic factors of value amongst other biomarkers analyzed in patients with recurrent high-grade glioma treated with either TMZ or PCV. TMZ and PCV did prove to be effective in certain cultured cell studies where tumors with wild type TP53 and MGMT methylation presented with increased sensitivity to alkylating agents such as the aforementioned anti-cancer drugs.

However, in the end, MGMT methylation analysis did not yield strong evidence of whether patients were more likely to respond to TMZ or PCV. Every study has its strengths and weaknesses and the above study’s weaknesses came in the form of several limitations. One of the limitations was that consent for some tumor tissue samples was not obtained or refused.

Another limitation was that the histopathology department themselves would decline or were unable to retrieve tumor tissue samples as well. The inability of tumor tissue acquisition leads to insufficient material needed for analysis on the several biomarkers that were tested. In addition, without sufficient tumor sample numbers, the sample size of this trial is also severely diminished in the ability to compare and analyze the prognostic effects of TMZ over PCV in regard to MGMT methylation and IDH1/2 mutation. Due to the detriment in sample size, I would not be able to repeat the experiment since I do not know if the trials conducted were an accurate representation of the two drugs studied. The prominent strength of this study was that it was a randomized control trial and that it also analyzed and compared other existing natural biomarkers to have a more overall view of the prognostic value for survival. This importance of this topic to medicine and pharmacy lies in the prospect of cancer itself. There still is not a cure for cancer, and brain cancer is one of the many, rare, but devastating forms of the disease out there that can impair and debilitate an array of cognitive functions. Thus, there are hundreds of clinical trials being performed in order to determine not only the best form of treatment in patient tolerability, but also the most effective form of treatment aimed at tumor reduction and eventual elimination — this study helped to dismiss a potential answer (MGMT methylation) for whether TMZ or PCV was the best form of chemotherapy to administer and encourages researchers to look into other chemotherapy alternatives. The research article can be categorized as Disease Oriented Medicine (DOE) because the study focused on laboratory test results from biomarkers and tissue sample analysis.

Both TMZ and PCV are standardized forms of anti-cancer chemotherapy drugs that are given in the event of HGG and both drugs seem to be equally as promising. The study demonstrated that neither one is more effective than the other, nor was one worse than the other when measured against MGMT methylation. Thus, other factors such as tolerability and cost should be taken into consideration when deciding which chemotherapy is best for treating HGG. Although, MGMT methylation and IDH1/2 mutation did not prove the preferred use of TMZ over PCV, it did open up findings that further supported MGMT methylation and IDH1/2 mutations to be of significant prognostic factors.