Glioblastoma Therapy: Going Beyond Hercules Columns
Glioblastoma Therapy: Going Beyond Hercules Columns
Glioblastoma multiforme is the most common primary brain tumor in adults. Median survival from the time of diagnosis is 14 months, with less than 5% of patients surviving 5 years. Despite advances in deciphering the complex biology of these tumors, the overall prognosis has only slightly improved in the past three decades. The clinical failure of many therapeutic approaches can be explained by the following considerations: the location of tumors within the brain presents a special set of challenges, including ability of drugs to cross the BBB; cancer cells have unstable genetic structures, very susceptible to mutations; cancer cells have an amalgam of different genetic defects that respond in different ways to any given treatment agent; and, infiltrating and apparently normal but 'activated' cells are evident in the brain surrounding the main tumor. In this way, the biologic phenomena of the 'normal brain' adjacent to the enhanced tumor could allow us to understand the first steps of cancerogenesis and, consequently, to interfere with the pathways responsible for tumor growth and recurrence.
Glioblastoma (GBM) is the most common primary brain tumor in adults. Primary GBM, which comprises more than 90% of cases, arises de novo, whereas secondary GBM progresses from previously diagnosed low-grade gliomas. Despite implementation of intensive therapeutic strategies and supportive care, patients with newly diagnosed GBM have a median survival of approximately 14 months from intervention, with a 5-year survival rate of less than 5%.
Molecular studies have identified important genetic events in human GBMs, including the following: inactivation of the p53 and retinoblastoma tumor suppressor pathways; dysregulation of growth factor signaling via amplification and mutational activation of receptor tyrosine kinase genes; and, activation of the phosphatidylinositol-3-OH kinase and the MAPK pathway. Recently, two key papers from Vogelstein's lab identified a highly interconnected network of aberrations (Figure 1), including three major pathways: receptor tyrosine kinase signaling and the p53/retinoblastoma tumor suppressor pathways. Moreover, these authors identified IDH1 mutations and their potential clinical importance. First, mutations in IDH1 preferentially occurred in younger GBM patients. Second, mutations in IDH1 were found in nearly all of the patients with secondary GBMs (mutations in five of six secondary GBM patients, compared with seven of 99 patients with primary GBMs). Third, patients with IDH1 mutations had a significantly improved prognosis, with a median overall survival of 3.8 years compared with 1.1 years for patients with wild-type IDH1.
(Enlarge Image)
Figure 1.
Genetic alterations and pathways involved in tumorigenesis.
a: Amplification; d: Deletion; EGFR: EGF receptor; m: Mutation; PDGFRA: Platelet derived growth factor receptor α; RB: Retinoblastoma tumor suppressor protein. Modified with permission from Cancer Genome Atlas Research Network.
Surgery should be the first therapeutic modality for GBM and the optimal goal is complete resection. Gross tumor resection immediately decompresses the brain and, due to the consequent reduction in neoplastic cells in the surgical cavity, probably increases the likelihood of response to radiotherapy and/or chemotherapy; it may, moreover, delay progression. Therefore, all patients should undergo tumor resection that is as extensive as possible. However, as GBM is infiltrative, complete resection is virtually impossible and relapse is almost inevitable. The extent of surgery is limited by the extensiveness of the tumor and/or the presence of eloquent areas, and so these patients can only undergo partial resection, which makes a worse prognosis more likely. Postoperative external beam radiation delivered conformally to the tumor volume (now commonly determined by both MRI contrast-enhancement and surrounding T2 signal hyperintensity) is now standard adjuvant treatment for GBM; 60 Gy in 30 fractions are delivered for a total of 6 weeks, to a target volume defined as a 2–3 cm ring of tissue surrounding the perimeter of the contrast-enhancing lesion. A randomized study conducted on 77 GBM patients older than the age of 70 years has demonstrated a survival advantage of radiotherapy over the best supportive care, without reducing the quality of life or cognition. The use of radioenhancers is still being investigated. Motexafin gadolinium (MGd) is a putative radiation enhancer initially evaluated in patients with brain metastases. In a preliminary Phase I trial study, MGd was administered in a 2–6-week course (10–22 doses) concomitant with radiotherapy in patients with GBM, demonstrating a median survival of 17.6 months. In a case-matched analysis, the MGd patients had a median survival of 16.1 months (n = 31), compared with the matched Radiation Therapy Oncology Group database patients, with a median survival of 11.8 months.
In the last 40 years, several randomized clinical trials have examined the role of adjuvant chemotherapy in improving the survival of brain tumor patients. Chemotherapeutic agents have been administered before ('neo-adjuvant'), during ('concomitant') or after ('adjuvant') radiotherapy. The addition of temozolomide to radiotherapy, resulting in a survival benefit with minimal additional toxicity, has become the standard treatment for newly diagnosed GBM. Methylguanine methyltransferase (MGMT) excision repair enzyme has been associated with tumor resistance, because it may reverse, in part, the impact of alkylating drugs by removing alkyl groups from the O6 position of guanine. Inactivation of the MGMT gene in the tumor tissue by methylation of the promoter region has been associated with good outcomes in malignant glioma. The final results of a trial with a median follow-up of more than 5 years, demonstrated that the methylation of the MGMT promoter is the strongest predictor for the outcome and benefit of temozolomide chemotherapy. Temozolomide has proved to be a proautophagic cytotoxic drug. Several potential common targets in apoptosis and autophagy resistance pathways, specifically, mTOR, class I PI3K and Akt, have been identified in GBM. The same authors found that temozolomide decreased the expression levels of hypoxia inducible factor-1α, ID-1, ID-2 and c-Myc in the glioma models that they investigated, all of which played major roles in angiogenesis and the switch to hypoxic metabolism. These changes could be at least partly responsible for the impairment of angiogenesis. The current standard of care, that is, the Stupp protocol, has led to a significant improvement in patient survival. This protocol consists of radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150–200 mg per square meter for 5 days during each 28-day cycle). However, following the introduction of the new standard of care for newly diagnosed GBM patients, with radiotherapy and concomitant/adjuvant temozolomide, new first- and second-line treatments are under evaluation. For this reason, even in the absence of clear data, a nitrosourea-based chemotherapy should be considered as a reasonable option, as well as a temozolomide rechallenge for patients that did not progress during temozolomide treatment.
Abstract and Introduction
Abstract
Glioblastoma multiforme is the most common primary brain tumor in adults. Median survival from the time of diagnosis is 14 months, with less than 5% of patients surviving 5 years. Despite advances in deciphering the complex biology of these tumors, the overall prognosis has only slightly improved in the past three decades. The clinical failure of many therapeutic approaches can be explained by the following considerations: the location of tumors within the brain presents a special set of challenges, including ability of drugs to cross the BBB; cancer cells have unstable genetic structures, very susceptible to mutations; cancer cells have an amalgam of different genetic defects that respond in different ways to any given treatment agent; and, infiltrating and apparently normal but 'activated' cells are evident in the brain surrounding the main tumor. In this way, the biologic phenomena of the 'normal brain' adjacent to the enhanced tumor could allow us to understand the first steps of cancerogenesis and, consequently, to interfere with the pathways responsible for tumor growth and recurrence.
Introduction
Glioblastoma (GBM) is the most common primary brain tumor in adults. Primary GBM, which comprises more than 90% of cases, arises de novo, whereas secondary GBM progresses from previously diagnosed low-grade gliomas. Despite implementation of intensive therapeutic strategies and supportive care, patients with newly diagnosed GBM have a median survival of approximately 14 months from intervention, with a 5-year survival rate of less than 5%.
Molecular studies have identified important genetic events in human GBMs, including the following: inactivation of the p53 and retinoblastoma tumor suppressor pathways; dysregulation of growth factor signaling via amplification and mutational activation of receptor tyrosine kinase genes; and, activation of the phosphatidylinositol-3-OH kinase and the MAPK pathway. Recently, two key papers from Vogelstein's lab identified a highly interconnected network of aberrations (Figure 1), including three major pathways: receptor tyrosine kinase signaling and the p53/retinoblastoma tumor suppressor pathways. Moreover, these authors identified IDH1 mutations and their potential clinical importance. First, mutations in IDH1 preferentially occurred in younger GBM patients. Second, mutations in IDH1 were found in nearly all of the patients with secondary GBMs (mutations in five of six secondary GBM patients, compared with seven of 99 patients with primary GBMs). Third, patients with IDH1 mutations had a significantly improved prognosis, with a median overall survival of 3.8 years compared with 1.1 years for patients with wild-type IDH1.
(Enlarge Image)
Figure 1.
Genetic alterations and pathways involved in tumorigenesis.
a: Amplification; d: Deletion; EGFR: EGF receptor; m: Mutation; PDGFRA: Platelet derived growth factor receptor α; RB: Retinoblastoma tumor suppressor protein. Modified with permission from Cancer Genome Atlas Research Network.
Surgery should be the first therapeutic modality for GBM and the optimal goal is complete resection. Gross tumor resection immediately decompresses the brain and, due to the consequent reduction in neoplastic cells in the surgical cavity, probably increases the likelihood of response to radiotherapy and/or chemotherapy; it may, moreover, delay progression. Therefore, all patients should undergo tumor resection that is as extensive as possible. However, as GBM is infiltrative, complete resection is virtually impossible and relapse is almost inevitable. The extent of surgery is limited by the extensiveness of the tumor and/or the presence of eloquent areas, and so these patients can only undergo partial resection, which makes a worse prognosis more likely. Postoperative external beam radiation delivered conformally to the tumor volume (now commonly determined by both MRI contrast-enhancement and surrounding T2 signal hyperintensity) is now standard adjuvant treatment for GBM; 60 Gy in 30 fractions are delivered for a total of 6 weeks, to a target volume defined as a 2–3 cm ring of tissue surrounding the perimeter of the contrast-enhancing lesion. A randomized study conducted on 77 GBM patients older than the age of 70 years has demonstrated a survival advantage of radiotherapy over the best supportive care, without reducing the quality of life or cognition. The use of radioenhancers is still being investigated. Motexafin gadolinium (MGd) is a putative radiation enhancer initially evaluated in patients with brain metastases. In a preliminary Phase I trial study, MGd was administered in a 2–6-week course (10–22 doses) concomitant with radiotherapy in patients with GBM, demonstrating a median survival of 17.6 months. In a case-matched analysis, the MGd patients had a median survival of 16.1 months (n = 31), compared with the matched Radiation Therapy Oncology Group database patients, with a median survival of 11.8 months.
In the last 40 years, several randomized clinical trials have examined the role of adjuvant chemotherapy in improving the survival of brain tumor patients. Chemotherapeutic agents have been administered before ('neo-adjuvant'), during ('concomitant') or after ('adjuvant') radiotherapy. The addition of temozolomide to radiotherapy, resulting in a survival benefit with minimal additional toxicity, has become the standard treatment for newly diagnosed GBM. Methylguanine methyltransferase (MGMT) excision repair enzyme has been associated with tumor resistance, because it may reverse, in part, the impact of alkylating drugs by removing alkyl groups from the O6 position of guanine. Inactivation of the MGMT gene in the tumor tissue by methylation of the promoter region has been associated with good outcomes in malignant glioma. The final results of a trial with a median follow-up of more than 5 years, demonstrated that the methylation of the MGMT promoter is the strongest predictor for the outcome and benefit of temozolomide chemotherapy. Temozolomide has proved to be a proautophagic cytotoxic drug. Several potential common targets in apoptosis and autophagy resistance pathways, specifically, mTOR, class I PI3K and Akt, have been identified in GBM. The same authors found that temozolomide decreased the expression levels of hypoxia inducible factor-1α, ID-1, ID-2 and c-Myc in the glioma models that they investigated, all of which played major roles in angiogenesis and the switch to hypoxic metabolism. These changes could be at least partly responsible for the impairment of angiogenesis. The current standard of care, that is, the Stupp protocol, has led to a significant improvement in patient survival. This protocol consists of radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150–200 mg per square meter for 5 days during each 28-day cycle). However, following the introduction of the new standard of care for newly diagnosed GBM patients, with radiotherapy and concomitant/adjuvant temozolomide, new first- and second-line treatments are under evaluation. For this reason, even in the absence of clear data, a nitrosourea-based chemotherapy should be considered as a reasonable option, as well as a temozolomide rechallenge for patients that did not progress during temozolomide treatment.
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