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JAMA Feb 2023Malignant primary brain tumors cause more than 15 000 deaths per year in the United States. The annual incidence of primary malignant brain tumors is approximately 7... (Review)
Review
IMPORTANCE
Malignant primary brain tumors cause more than 15 000 deaths per year in the United States. The annual incidence of primary malignant brain tumors is approximately 7 per 100 000 individuals and increases with age. Five-year survival is approximately 36%.
OBSERVATIONS
Approximately 49% of malignant brain tumors are glioblastomas, and 30% are diffusely infiltrating lower-grade gliomas. Other malignant brain tumors include primary central nervous system (CNS) lymphoma (7%) and malignant forms of ependymomas (3%) and meningiomas (2%). Symptoms of malignant brain tumors include headache (50%), seizures (20%-50%), neurocognitive impairment (30%-40%), and focal neurologic deficits (10%-40%). Magnetic resonance imaging before and after a gadolinium-based contrast agent is the preferred imaging modality for evaluating brain tumors. Diagnosis requires tumor biopsy with consideration of histopathological and molecular characteristics. Treatment varies by tumor type and often includes a combination of surgery, chemotherapy, and radiation. For patients with glioblastoma, the combination of temozolomide with radiotherapy improved survival when compared with radiotherapy alone (2-year survival, 27.2% vs 10.9%; 5-year survival, 9.8% vs 1.9%; hazard ratio [HR], 0.6 [95% CI, 0.5-0.7]; P < .001). In patients with anaplastic oligodendroglial tumors with 1p/19q codeletion, probable 20-year overall survival following radiotherapy without vs with the combination of procarbazine, lomustine, and vincristine was 13.6% vs 37.1% (80 patients; HR, 0.60 [95% CI, 0.35-1.03]; P = .06) in the EORTC 26951 trial and 14.9% vs 37% in the RTOG 9402 trial (125 patients; HR, 0.61 [95% CI, 0.40-0.94]; P = .02). Treatment of primary CNS lymphoma includes high-dose methotrexate-containing regimens, followed by consolidation therapy with myeloablative chemotherapy and autologous stem cell rescue, nonmyeloablative chemotherapy regimens, or whole brain radiation.
CONCLUSIONS AND RELEVANCE
The incidence of primary malignant brain tumors is approximately 7 per 100 000 individuals, and approximately 49% of primary malignant brain tumors are glioblastomas. Most patients die from progressive disease. First-line therapy for glioblastoma is surgery followed by radiation and the alkylating chemotherapeutic agent temozolomide.
Topics: Adult; Humans; Antineoplastic Combined Chemotherapy Protocols; Brain; Brain Neoplasms; Glioblastoma; Glioma; Lymphoma; Temozolomide
PubMed: 36809318
DOI: 10.1001/jama.2023.0023 -
American Family Physician Jan 2020Lymphoma is a group of malignant neoplasms of lymphocytes with more than 90 subtypes. It is traditionally classified broadly as non-Hodgkin or Hodgkin lymphoma.... (Review)
Review
Lymphoma is a group of malignant neoplasms of lymphocytes with more than 90 subtypes. It is traditionally classified broadly as non-Hodgkin or Hodgkin lymphoma. Approximately 82,000 new U.S. patients are diagnosed with lymphoma annually. Any tobacco use and obesity are major modifiable risk factors, with genetic, infectious, and inflammatory etiologies also contributing. Lymphoma typically presents as painless adenopathy, with systemic symptoms of fever, unexplained weight loss, and night sweats occurring in more advanced stages of the disease. An open lymph node biopsy is preferred for diagnosis. The Lugano classification system incorporates symptoms and the extent of the disease as shown on positron emission tomography/computed tomography to stage lymphoma, which is then used to determine treatment. Chemotherapy treatment plans differ between the main subtypes of lymphoma. Non-Hodgkin lymphoma is treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab (R-CHOP), bendamustine, and lenalidomide. Hodgkin lymphoma is treated with combined chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), Stanford V (a chemotherapy regimen consisting of mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone), or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) with radiotherapy. Subsequent chemotherapy toxicities include neuropathy, cardiotoxicity, and secondary cancers such as lung and breast, and should be considered in the shared decision-making process to select a treatment regimen. Once remission is achieved, patients need routine surveillance to monitor for complications and relapse, in addition to age-appropriate screenings recommended by the U.S. Preventive Services Task Force. Patients should receive a 13-valent pneumococcal conjugate vaccine followed by a 23-valent pneumococcal polysaccharide vaccine at least eight weeks later with additional age-appropriate vaccinations because lymphoma is an immunosuppressive condition. Household contacts should also be current with their immunizations.
Topics: Adult; Aged; Antineoplastic Agents; Biopsy; Evidence-Based Medicine; Female; Humans; Lymphoma; Male; Middle Aged; Neoplasm Staging; Risk Factors; United States
PubMed: 31894937
DOI: No ID Found -
Current Treatment Options in Oncology Nov 2022Primary CNS lymphoma (PCNSL) constitutes a rare extranodal variant of non-Hodgkin lymphoma (NHL) with an annual incidence of 0.45/100,000. Given the paucity of large... (Review)
Review
Primary CNS lymphoma (PCNSL) constitutes a rare extranodal variant of non-Hodgkin lymphoma (NHL) with an annual incidence of 0.45/100,000. Given the paucity of large prospective clinical trials, there is no consensus treatment for refractory or relapsed (r/r) PCNSL, and available strategies are largely based on retrospective analyses. Patient age, performance status, previously administered treatment, duration of response, and molecular characteristics guide selection of salvage therapy. Patients with a good performance status (KPS >70), particularly ≤65 years, and adequate organ function should be considered for salvage polychemotherapy. Based on its high overall response rate even in the relapsed setting, we choose high-dose (≥ 3.5g/m) methotrexate (HD-MTX) based regimens, e.g., R-MPV (rituximab, HD-MTX, procarbazine, and vincristine), for remission re-induction as long as patients were sensitive to first line HD-MTX-based regimens, especially when duration of previous response was ≥ 1 year. Following successful remission induction, we choose myeloablative chemotherapy (e.g., thiotepa, busulfan, cyclophosphamide) and subsequent autologous stem cell transplant in curative intent whenever feasible. Alternatively, conventional chemotherapy regimens (for example, monthly HD-MTX) or low-dose whole-brain radiation therapy (WBRT) are selected for consolidation in non-transplant candidates in complete remission. In cases of HD-MTX refractory disease or contraindications, we use pemetrexed; temozolomide/rituximab; high-dose cytarabine; or whole brain radiation for remission induction. Clinical trial participation is considered as well. Emerging therapies for upfront or salvage therapy under ongoing investigation include bruton tyrosine kinase inhibition (e.g., ibrutinib), immunomodulatory drugs (e.g., lenalidomide), immune checkpoint inhibitors (ICI, e.g., nivolumab), and chimeric antigen receptor T (CAR-T) cell therapy.
Topics: Humans; Thiotepa; Busulfan; Rituximab; Central Nervous System Neoplasms; Agammaglobulinaemia Tyrosine Kinase; Receptors, Chimeric Antigen; Methotrexate; Vincristine; Brain Neoplasms; Retrospective Studies; Lenalidomide; Pemetrexed; Nivolumab; Temozolomide; Immune Checkpoint Inhibitors; Procarbazine; Prospective Studies; Antineoplastic Combined Chemotherapy Protocols; Cranial Irradiation; Lymphoma, Non-Hodgkin; Cytarabine; Cyclophosphamide
PubMed: 36205806
DOI: 10.1007/s11864-022-01016-5 -
The Cochrane Database of Systematic... May 2021Glioblastoma (GBM) is a highly malignant brain tumour that almost inevitably progresses or recurs after first line standard of care. There is no consensus regarding the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Glioblastoma (GBM) is a highly malignant brain tumour that almost inevitably progresses or recurs after first line standard of care. There is no consensus regarding the best treatment/s to offer people upon disease progression or recurrence. For the purposes of this review, progression and recurrence are considered as one entity.
OBJECTIVES
To evaluate the effectiveness of further treatment/s for first and subsequent progression or recurrence of glioblastoma (GBM) among people who have received the standard of care (Stupp protocol) for primary treatment of the disease; and to prepare a brief economic commentary on the available evidence.
SEARCH METHODS
We searched MEDLINE and Embase electronic databases from 2005 to December 2019 and the Cochrane Central Register of Controlled Trials (CENTRAL, in the Cochrane Library; Issue 12, 2019). Economic searches included the National Health Service Economic Evaluation Database (NHS EED) up to 2015 (database closure) and MEDLINE and Embase from 2015 to December 2019.
SELECTION CRITERIA
Randomised controlled trials (RCTs) and comparative non-randomised studies (NRSs) evaluating effectiveness of treatments for progressive/recurrent GBM. Eligible studies included people with progressive or recurrent GBM who had received first line radiotherapy with concomitant and adjuvant temozolomide (TMZ).
DATA COLLECTION AND ANALYSIS
Two review authors independently selected studies and extracted data to a pre-designed data extraction form. We conducted network meta-analyses (NMA) and ranked treatments according to effectiveness for each outcome using the random-effects model and Stata software (version 15). We rated the certainty of evidence using the GRADE approach.
MAIN RESULTS
We included 42 studies: these comprised 34 randomised controlled trials (RCTs) and 8 non-randomised studies (NRSs) involving 5236 participants. We judged most RCTs to be at a low risk of bias and NRSs at high risk of bias. Interventions included chemotherapy, re-operation, re-irradiation and novel therapies either used alone or in combination. For first recurrence, we included 11 interventions in the network meta-analysis (NMA) for overall survival (OS), and eight in the NMA for progression-free survival (PFS). Lomustine (LOM; also known as CCNU) was the most common comparator and was used as the reference treatment. No studies in the NMA evaluated surgery, re-irradiation, PCV (procarbazine, lomustine, vincristine), TMZ re-challenge or best supportive care. We could not perform NMA for second or later recurrence due to insufficient data. Quality-of-life data were sparse. First recurrence (NMA findings) Median OS across included studies in the NMA ranged from 5.5 to 12.6 months and median progression-free survival (PFS) ranged from 1.5 months to 4.2 months. We found no high-certainty evidence that any treatments tested were better than lomustine. These treatments included the following. Bevacizumab plus lomustine: Evidence suggested probably little or no difference in OS between bevacizumab (BEV) combined with lomustine (LOM) and LOM monotherapy (hazard ratio (HR) 0.91, 0.75 to 1.10; moderate-certainty evidence), although BEV + LOM may improve PFS (HR 0.57, 95% confidence interval (CI) 0.44 to 0.74; low-certainty evidence). Bevacizumab monotherapy: Low-certainty evidence suggested there may be little or no difference in OS (HR 1.22, 95% CI 0.84 to 1.76) and PFS (HR 0.90, 95% CI 0.58 to 1.38; low-certainty evidence) between BEV and LOM monotherapies; more evidence on BEV is needed. Regorafenib (REG): REG may improve OS compared with LOM (HR 0.50, 95% CI 0.33 to 0.76; low-certainty evidence). Evidence on PFS was very low certainty and more evidence on REG is needed. Temozolomide (TMZ) plus Depatux-M (ABT414): For OS, low-certainty evidence suggested that TMZ plus ABT414 may be more effective than LOM (HR 0.66, 95% CI 0.47 to 0.92) and may be more effective than BEV (HR 0.54, 95% CI 0.33 to 0.89; low-certainty evidence). This may be due to the TMZ component only and more evidence is needed. Fotemustine (FOM): FOM and LOM may have similar effects on OS (HR 0.89, 95% CI 0.51 to 1.57, low-certainty evidence). Bevacizumab and irinotecan (IRI): Evidence on BEV + irinotecan (IRI) versus LOM for both OS and PFS is very uncertain and there is probably little or no difference between BEV + IRI versus BEV monotherapy (OS: HR 0.95, 95% CI 0.70 to 1.30; moderate-certainty evidence). When treatments were ranked for OS, FOM ranked first, BEV + LOM second, LOM third, BEV + IRI fourth, and BEV fifth. Ranking does not take into account the certainty of the evidence, which also suggests there may be little or no difference between FOM and LOM. Other treatments Three studies evaluated re-operation versus no re-operation, with or without re-irradiation and chemotherapy, and these suggested possible survival advantages with re-operation within the context of being able to select suitable candidates for re-operation. A cannabinoid treatment in the early stages of evaluation, in combination with TMZ, merits further evaluation. Second or later recurrence Limited evidence from three heterogeneous studies suggested that radiotherapy with or without BEV may have a beneficial effect on survival but more evidence is needed. Evidence was insufficient to draw conclusions about the best radiotherapy dosage. Other evidence suggested that there may be little difference in survival with tumour-treating fields compared with physician's best choice of treatment. We found no reliable evidence on best supportive care. Severe adverse events (SAEs) The BEV+LOM combination was associated with significantly greater risk of SAEs than LOM monotherapy (RR 2.51, 95% CI 1.72 to 3.66, high-certainty evidence), and ranked joint worst with cediranib + LOM (RR 2.51, 95% CI 1.29 to 4.90; high-certainty evidence). LOM ranked best and REG ranked second best. Adding novel treatments to BEV was generally associated with a higher risk of severe adverse events compared with BEV alone.
AUTHORS' CONCLUSIONS
For treatment of first recurrence of GBM, among people previously treated with surgery and standard chemoradiotherapy, the combination treatments evaluated did not improve overall survival compared with LOM monotherapy and were often associated with a higher risk of severe adverse events. Limited evidence suggested that re-operation with or without re-irradiation and chemotherapy may be suitable for selected candidates. Evidence on second recurrence is sparse. Re-irradiation with or without bevacizumab may be of value in selected individuals, but more evidence is needed.
Topics: Brain Neoplasms; Glioblastoma; Humans; Lomustine; Neoplasm Recurrence, Local; Network Meta-Analysis
PubMed: 34559423
DOI: 10.1002/14651858.CD013579.pub2 -
Cancer Treatment Reviews Jul 2020Glioblastomas are the most common malignant primary intrinsic brain tumors. Their incidence increases with age, and males are more often affected. First-line management... (Review)
Review
Glioblastomas are the most common malignant primary intrinsic brain tumors. Their incidence increases with age, and males are more often affected. First-line management includes maximum safe surgical resection followed by involved-field radiotherapy plus concomitant and six cycles of maintenance temozolomide chemotherapy. Standards of care at recurrence are much less well defined. Minorities of patients are offered second surgery or re-irradiation, but data on a positive impact on survival from randomized trials are lacking. The majority of patients who are eligible for salvage therapy receive systemic treatment, mostly with nitrosourea-based regimens or, depending on availability, bevacizumab alone or in various combinations. In clinical trials, lomustine alone has been increasingly used as a control arm, assigning this drug a standard-of-care position in the setting of recurrent glioblastoma. Here we review the activity of lomustine in the treatment of diffuse gliomas of adulthood in various settings. The most compelling data for lomustine stem from three randomized trials when lomustine was combined with procarbazine and vincristine as the PCV regimen in the newly diagnosed setting together with radiotherapy; improved survival with PCV was restricted to patients with isocitrate dehydrogenase-mutant tumors. No other agent with the possible exception of regorafenib has shown superior activity to lomustine in recurrent glioblastoma, but activity is largely restricted to patients with tumors with O-methylguanine DNA methyltransferase (MGMT) promoter methylation. Hematological toxicity, notably thrombocytopenia often limits adequate exposure.
Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Glioblastoma; Humans; Lomustine; Neoplasm Recurrence, Local; Randomized Controlled Trials as Topic
PubMed: 32408220
DOI: 10.1016/j.ctrv.2020.102029 -
Journal of Clinical Oncology : Official... Feb 2022To provide guidance to clinicians regarding therapy for diffuse astrocytic and oligodendroglial tumors in adults.
PURPOSE
To provide guidance to clinicians regarding therapy for diffuse astrocytic and oligodendroglial tumors in adults.
METHODS
ASCO and the Society for Neuro-Oncology convened an Expert Panel and conducted a systematic review of the literature.
RESULTS
Fifty-nine randomized trials focusing on therapeutic management were identified.
RECOMMENDATIONS
Adults with newly diagnosed oligodendroglioma, isocitrate dehydrogenase (IDH)-mutant, 1p19q codeleted CNS WHO grade 2 and 3 should be offered radiation therapy (RT) and procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ) is a reasonable alternative for patients who may not tolerate PCV, but no high-level evidence supports upfront TMZ in this setting. People with newly diagnosed astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 2 should be offered RT with adjuvant chemotherapy (TMZ or PCV). People with astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 should be offered RT and adjuvant TMZ. People with astrocytoma, IDH-mutant, CNS WHO grade 4 may follow recommendations for either astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 or glioblastoma, IDH-wildtype, CNS WHO grade 4. Concurrent TMZ and RT should be offered to patients with newly diagnosed glioblastoma, IDH-wildtype, CNS WHO grade 4 followed by 6 months of adjuvant TMZ. Alternating electric field therapy, approved by the US Food and Drug Administration, should be considered for these patients. Bevacizumab is not recommended. In situations in which the benefits of 6-week RT plus TMZ may not outweigh the harms, hypofractionated RT plus TMZ is reasonable. In patients age ≥ 60 to ≥ 70 years, with poor performance status or for whom toxicity or prognosis are concerns, best supportive care alone, RT alone (for promoter unmethylated tumors), or TMZ alone (for promoter methylated tumors) are reasonable treatment options. Additional information is available at www.asco.org/neurooncology-guidelines.
Topics: Astrocytoma; Brain Neoplasms; Clinical Decision-Making; Consensus; Evidence-Based Medicine; Humans; Medical Oncology; Oligodendroglioma; Predictive Value of Tests; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome
PubMed: 34898238
DOI: 10.1200/JCO.21.02036 -
The Lancet. Oncology Jan 2022Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment... (Comparative Study)
Comparative Study Randomized Controlled Trial
Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma (EuroNet-PHL-C1): a titration study with an open-label, embedded, multinational, non-inferiority, randomised...
BACKGROUND
Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity.
METHODS
Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m etoposide taken intravenously on days 1-5; 60 mg/m prednisone taken orally on days 1-15; and 40 mg/m doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m prednisone taken orally on days 1 to 15; and 100 mg/m procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy analyses are reported per protocol and safety in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (trial number NCT00433459) and EUDRACT (trial number 2006-000995-33), and is closed to recruitment.
FINDINGS
Between Jan 31, 2007, and Jan 30, 2013, 2102 patients were recruited. 737 (35%) of the 2102 recruited patients were in treatment group 1 (early-stage disease) and were not included in our analysis. 1365 (65%) of the 2102 patients were in treatment group 2 (intermediate-stage disease; n=455) and treatment group 3 (advanced-stage disease; n=910). Of these 1365, 1287 (94%) patients (435 [34%] of 1287 in treatment group 2 and 852 [66%] of 1287 in treatment group 3) were included in the titration trial per-protocol analysis. 937 (69%) of 1365 patients were randomly assigned to COPP (n=471) or COPDAC (n=466) in the embedded trial. Median follow-up was 66·5 months (IQR 62·7-71·7). Of 1287 patients in the per-protocol group, 514 (40%) had an adequate response to treatment and were not treated with radiotherapy (215 [49%] of 435 in treatment group 2 and 299 [35%] of 852 in treatment group 3). 773 (60%) of 1287 patients with inadequate response were scheduled for radiotherapy (220 [51%] of 435 in the treatment group 2 and 553 [65%] of 852 in treatment group 3. In patients who responded adequately, event-free survival rates at 5 years were 90·1% (95% CI 87·5-92·7). event-free survival rates at 5 years in 892 patients who were randomly assigned to treatment and analysed per protocol were 89·9% (95% CI 87·1-92·8) for COPP (n=444) versus 86·1% (82·9-89·4) for COPDAC (n=448). The COPDAC minus COPP difference in event-free survival at 5 years was -3·7% (-8·0 to 0·6). The most common grade 3-4 adverse events (intention-to-treat population) were decreased haemoglobin (205 [15%] of 1365 patients during OEPA vs 37 [7%] of 528 treated with COPP vs 20 [2%] of 819 treated with COPDAC), decreased white blood cells (815 [60%] vs 231 [44%] vs 84 [10%]), and decreased neutrophils (1160 [85%] vs 223 [42%] vs 174 [21%]). One patient in treatment group 2 died of sepsis after the first cycle of OEPA; no other treatment-related deaths occurred.
INTERPRETATION
Our results show that radiotherapy can be omitted in patients who adequately respond to treatment, when consolidated with COPP or COPDAC. COPDAC might be less effective, but is substantially less gonadotoxic than COPP. A high proportion of patients could therefore be spared radiotherapy, eventually reducing the late effects of treatment. With more refined criteria for response assessment, the number of patients who receive radiotherapy will be further decreased.
FUNDING
Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder Gießen, Kinderkrebsstiftung Mainz, Tour der Hoffnung, Menschen für Kinder, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Cyclophosphamide; Female; Follicle Stimulating Hormone; Hodgkin Disease; Humans; Male; Neoplasm Staging; Prednisone; Procarbazine; Vincristine
PubMed: 34895479
DOI: 10.1016/S1470-2045(21)00470-8 -
International Journal of Molecular... May 2022One of the biggest challenges in neuro-oncology is understanding the complexity of central nervous system tumors, such as gliomas, in order to develop suitable... (Review)
Review
One of the biggest challenges in neuro-oncology is understanding the complexity of central nervous system tumors, such as gliomas, in order to develop suitable therapeutics. Conventional therapies in malignant gliomas reconcile surgery and radiotherapy with the use of chemotherapeutic options such as temozolomide, chloroethyl nitrosoureas and the combination therapy of procarbazine, lomustine and vincristine. With the unraveling of deregulated cancer cell signaling pathways, targeted therapies have been developed. The most affected signaling pathways in glioma cells involve tyrosine kinase receptors and their downstream pathways, such as the phosphatidylinositol 3-kinases (PI3K/AKT/mTOR) and mitogen-activated protein kinase pathways (MAPK). MAPK pathway inhibitors include farnesyl transferase inhibitors, Ras kinase inhibitors and mitogen-activated protein extracellular regulated kinase (MEK) inhibitors, while PI3K/AKT/mTOR pathway inhibitors are divided into pan-inhibitors, PI3K/mTOR dual inhibitors and AKT inhibitors. The relevance of the immune system in carcinogenesis has led to the development of immunotherapy, through vaccination, blocking of immune checkpoints, oncolytic viruses, and adoptive immunotherapy using chimeric antigen receptor T cells. In this article we provide a comprehensive review of the signaling pathways underlying malignant transformation, the therapies currently used in the treatment of malignant gliomas and further explore therapies under development, including several ongoing clinical trials.
Topics: Glioma; Humans; Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases
PubMed: 35628161
DOI: 10.3390/ijms23105351