Strategic enhancement of immune checkpoint inhibition in refractory Colorectal Cancer: Trends and future prospective.

Colorectal cancer (CRC), known as a frequently fatal disease, ranking as the third most common malignancy, is the second leading cause of cancer related mortality worldwide. Metastases are common in CRC patients which account for approximately 25% of the patients at diagnosis, 50% of patients during treatment which is associated closely with CRC mortality. Conventional therapies such as surgery, chemotherapy, and radiotherapy are standards of care for the treatment of CRC patients. However, primary tumor recurrence and secondary disease in patients receiving standard of care treatment modalities occur in 50% of patients so that new treatment modalities are needed. Immune checkpoint inhibition (ICI) has transformed the management of patients suffered from metastatic CRC (mCRC) with mismatch repair deficiency (dMMR) and microsatellite instability (MSI) -high (MSI-H) while manifests ineffectiveness in preserved mismatch repair (pMMR) or microsatellite stable (MSS) "cold" tumors which makes up the majority (95%) of mCRC. In this review, we mainly lay emphasis on the development of combinations in therapy strategies with ICIs with other immune based treatment approaches to increase the intra-tumoral immune response and render tumors 'immune-reactive', thereby increasing the efficacy of tumor immunotherapy.

Progress and prospect in tumor treating fields treatment of glioblastoma.

Glioblastoma (GBM) is a challenging cancer with poor prognosis. The classical standard for treatment is safe resection, followed by concurrent chemoradiotherapy with subsequent adjuvant temozolomide (TMZ). Despite several attempts at different treatments, the 5-year survival rate remains poor. In recent years, with the continuous progress of treatment technology, tumor treating fields (TTFields) were preferable. The device could generate an intermediate frequency alternating electric field and induce apoptosis of some specific types of cancer cells with few toxic and side effects. TTFields induced apoptosis through multiple activations of the pathway. TTFields have been Food and Drug Administration (FDA)-approved for diagnosis and recurrent GBM as additional clinical trial results are revealed. This study reviewed the current status, mechanisms, correlations with immune pathways, the prospects of applying TTFields for GBM, and the adverse events.

No improvement in survival of older women with cervical cancer-A nationwide study.

AIM: This study aims to report trends in primary treatment and survival in cervical cancer (CC) to identify opportunities to improve clinical practice and disease outcome. METHODS: Patients diagnosed with CC between 1989 and 2018 were identified from the Netherlands Cancer Registry (N = 21,644). Trends in primary treatment and 5-year relative survival were analysed with the Cochran-Armitage trend test and multivariable Poisson regression, respectively. RESULTS: In early CC, surgery remains the preferred treatment for ages 15-74. Overall, it was applied more often in younger than in older patients (92% in 15-44; 64% in 65-74). For 75+, surgery use was stable over time (38%-41%, p=0.368), while administration of radiotherapy decreased (57%-29%, p < 0.001). In locally advanced CC, chemoradiation use increased over time (5%-65%, p < 0.001). It was applied least often for 75+, in which radiotherapy remains most common (54% in 2014-2018). In metastatic CC, chemotherapy use increased over time (11%-28%, p < 0.001), but varied across age groups (6%-40% in 2014-2018). In patients treated with primary chemoradiation, regardless of stage, brachytherapy use increased over time (p ≤ 0.001). Full cohort 5-year survival increased from 68% to 74% (relative excess risk 0.55; 95% confidence interval [0.50-0.62]). Increases were most significant in locally advanced CC (38%-60%; 0.55 [0.47-0.65]). Survival remained stable in 75+ (38%-34%; 0.82 [0.66-1.02]). CONCLUSION: Relative survival for cervical cancer increased over the last three decades. The proportion of older patients receiving preferred treatment lags behind. Consequently, survival did not improve in the oldest patients.

The immunopathogenesis and immunotherapy of cutaneous T cell lymphoma: Current and future approaches.

In the past few decades, immunotherapy has emerged as an effective therapeutic option for patients with cutaneous T cell lymphoma (CTCL). CTCL is characterized by progressive impairment of multiple arms of the immune system. Immunotherapy targets these deficits to stimulate a more robust antitumor response, thereby both clearing the malignant T cells and repairing the immune dysfunction. By potentiating rather than suppressing the immune system, immunotherapy can result in longer treatment responses than alternatives such as chemotherapy. In recent years, advances in our understanding of the pathogenesis of CTCL have led to the development of several new agents with promising efficacy profiles. The second article in this continuing medical education series describes the current immunotherapeutic options for treatment of CTCL, with a focus on how they interact with the immune system and their treatment outcomes in case studies and clinical trials. We will discuss established CTCL immunotherapies, such as interferons, photopheresis, and retinoids; emerging therapies, such as interleukin-12 and Toll-like receptor agonists; and new approaches to targeting tumor antigens and checkpoint molecules, such as mogamulizumab, anti-programmed cell death protein 1, anti-CD47, and chimeric antigen receptor T cell therapy. We also describe the principles of multimodality immunotherapy and the use of total skin electron beam therapy in such regimens.

Oligometastatic and Oligoprogression Disease and Local Therapies in Prostate Cancer.

Our understanding of metastatic disease is rapidly advancing, with recent evidence supporting an oligometastatic state currently defined by patients having a limited (typically ≤5) number of metastatic deposits. The optimal management of these patients is also shifting toward increased integration of local therapies, with emerging evidence suggesting metastasis-directed therapy can improve overall survival. Additionally, the use of stereotactic ablative radiation therapy within castration-sensitive oligometastatic prostate cancer cohorts appears to forestall the need to initiate systemic therapy, which has unfavorable side effect profiles, such as androgen deprivation therapy, while itself being associated with little toxicity. We review the literature surrounding the use of metastasis-directed therapy in the treatment of oligometastatic prostate cancer by reviewing the evidence for its use within 3 subgroups: de novo synchronous, oligorecurrent, and oligoprogressive disease.

Effect of GREM 1 gene on chemoradiotherapy sensitivity of cervical squamous carcinoma cells.

OBJECTIVE: To investigate the effect of GREM1 on the sensitivity of cervical squamous carcinoma cells to radiotherapy and chemotherapy. PATIENTS AND METHODS: The resected cancer tissues and paracancerous tissues of patients with cervical carcinoma were collected. The expressions of GREM1 protein and mRNA in SiHa cell line of cervical squamous carcinoma were tested by Western blot and reverse transcription-polymerase chain reaction (qRT-PCR). The effect of GREM1 on chemotherapy sensitivity of SiHa cells was tested by MTT assay. SiHa cells were irradiated with different doses of X-ray, and the changing trend of GREM1 in cell lines was observed. RESULTS: Compared with paracancerous tissues, the expression level of GREM1 in cervical squamous carcinoma was significantly higher than that in paracancerous tissues (p<0.05). After adding different concentrations of chemotherapeutic drugs, the relative survival rate of SiHa cells overexpressing GREM1 group was significantly increased. After high-energy X-ray irradiation with different radiation doses of SiHa cells, the expression levels of GREM1mRNA and protein in SiHa cell lines showed a significant downward trend. GREM1 was highly expressed in cervical squamous carcinoma. CONCLUSIONS: Down-regulating GREM1 expression can increase the chemotherapy sensitivity of SiHa cells. GREM1 may be related to the radiotherapy sensitivity of cervical squamous carcinoma.

The progress and confusion of anti-PD1/PD-L1 immunotherapy for patients with advanced non-small cell lung cancer.

Recently, immunotherapy has evolved into a true treatment modality with the approval of PD-1 and PD-L1 inhibitors as the standard care for first-line treatment in patients with non-small cell lung cancer (NSCLC). Until now, for patients with advanced NSCLC, treatment of targeting immune checkpoints reveals a promising survival benefit, and some patients even get long term survive, which creates a paradigm shift in NSCLC treatment. However, many issues or problems are also appearing in clinical practice, such as the lower overall efficacy rate (20-40%), treatment modes, populations choice of immunotherapy, drug resistance, and safety, etc. Thus, in this review, we will mainly summarize and discuss the recent development and confusion of PD-1/PD-L1 inhibitors for advanced NSCLC patients based on current clinical studies.

[Progress and prospects of international cancer drug clinical research on gastric cancer].

Gastric cancer is a common type of malignant tumor. Recently, a growing number of clinical researches initiated by investigators have provided valuable evidence for clinical practice. Here we review the perioperative treatment of locally advanced gastric cancer, and summarize the optimization of neoadjuvant treatment regimens, the exploration of new combinational treatment models and new adjuvant chemotherapy schemes, and the changes in the status of chemoradiotherapy in adjuvant therapy. At the same time, for the comprehensive treatment of advanced gastric cancer, the advances in the optimization of first-line chemotherapy regimens, emerging immunotherapy and targeted therapy are reviewed as well. Gastric cancer is a highly heterogeneous tumor. For further development of precision medicine represented by targeted therapy and immunotherapy, genetic testing-guided precise molecular subtyping will be the direction.

Metastatic Hormone-Sensitive Prostate Cancer: A Review of the Current Treatment Landscape.

PURPOSE: In recent years, the treatment options for metastatic hormone-sensitive prostate cancer (mHSPC) have expanded significantly. In addition to androgen deprivation therapy, the systemic treatments now include docetaxel, abiraterone, enzalutamide, and apalutamide. Radiation to the primary is also an option for select low-volume patients. METHODS: We conducted a review of the pivotal trials that have changed the practice of mHSPC. RESULTS: We describe an overview of the trials that investigated docetaxel (CHAARTED and STAMPEDE-Docetaxel), abiraterone (LATTITUDE and STAMPEDE-Abiraterone), enzalutamide (ARCHES, ENZAMET), apalutamide (TITAN), and radiation to the primary (STAMPEDE-Radiation). DISCUSSION: The treatment of mHSPC is a complex topic, and treatment choice should be individualized. Patient preferences, cost, volume of disease, and side effect profiles are important in determining which option is the best for an individual patient.

Treatment of Primary in Metastatic Prostate Cancer: What Is the Standard of Care?

Until recently, men with metastatic prostate cancer were commenced on androgen deprivation therapy at diagnosis, followed by sequential lines of treatment with the development of castration resistance. However, the results of recent clinical trials, which revealed that the addition of radiotherapy to the prostate to a dose of 55 to 60 Gy in 20 fractions over 4 weeks in patients with low-volume metastatic hormone-sensitive prostate cancer, in addition to androgen deprivation therapy and another systemic treatment option, either docetaxel, abiraterone, enzalutamide, or apalutamide, has led to a paradigm change in the management of this disease.

Impact of diffusing lung capacity before and after neoadjuvant concurrent chemoradiation on postoperative pulmonary complications among patients with stage IIIA/N2 non-small-cell lung cancer.

BACKGROUND AND OBJECTIVE: This study aims to evaluate the impact of diffusing capacity of the lung for carbon monoxide (DLco) before and after neoadjuvant concurrent chemoradiotherapy (CCRT) on postoperative pulmonary complication (PPC) among stage IIIA/N2 non-small-cell lung cancer (NSCLC) patients. METHODS: We retrospectively studied 324 patients with stage IIIA/N2 NSCLC between 2009 and 2016. Patients were classified into 4 groups according to DLco before and after neoadjuvant CCRT; normal-to-normal (NN), normal-to-low (NL), low-to-low (LL), and low-to-very low (LVL). Low DLco and very low DLco were defined as DLco < 80% predicted and DLco < 60% predicted, respectively. RESULTS: On average, DLco was decreased by 12.3% (±10.5) after CCRT. In multivariable-adjusted analyses, the incidence rate ratio (IRR) for any PPC comparing patients with low DLco to those with normal DLco before CCRT was 2.14 (95% confidence interval (CI) = 1.36-3.36). Moreover, the IRR for any PPC was 3.78 (95% CI = 1.68-8.49) in LVL group compared to NN group. The significant change of DLco after neoadjuvant CCRT had an additional impact on PPC, particularly after bilobectomy or pneumonectomy with low baseline DLco. CONCLUSIONS: The DLco before CCRT was significantly associated with risk of PPC, and repeated test of DLco after CCRT would be helpful for risk assessment, particularly in patients with low DLco before neoadjuvant CCRT.

Anal Squamous Cell Carcinoma: Radiation Therapy Alone Must Be Avoided.

BACKGROUND: Anal squamous cell carcinoma (ASCC) is the most common histological subtype of anal cancer. Rates have been observed to increase in recent years. Combined chemoradiotherapy (CCRT) is currently the gold standard of treatment. The aim of this study is to assess ASCC prevalence, treatment trends, and overall survival (OS) in the United States. METHODS: Patients diagnosed with stage I-IV ASCC were identified from the National Cancer Database from 2004 to 2015. The primary outcome was 5-year OS, which was analyzed using Kaplan-Meier survival curves, log-rank test, and Cox proportional hazards models. RESULTS: 34,613 cases were included (stage I: 21.45%; II: 41.00%; III: 31.62%; IV: 5.94%), with an increasing trend in prevalence. CCRT was the most used treatment. Multimodal treatment, combining surgery with CCRT, offered the best OS rates for stage I, II, and IV cancers (I: 84.87%; II: 75.12%; IV: 33.08%), comparable with survival of stage III patients treated with CCRT (III: 61.14%). Radiation alone had the worse OS rates, and on adjusted analysis, radiation treatment alone had the greatest risk of mortality (I: hazard ratio, 2.01; 95% confidence interval, 1.14-3.54; P = 0.016; II: 2.05, 1.44-2.93, P < 0.001; IV: 1.99, 0.99-4.02, P = 0.054). CONCLUSIONS: ASCC has increased in prevalence, notably in stage III and IV disease. Although CCRT is the most commonly used treatment type for all stages of ASCC, multimodal treatment offers better OS in stages I, II, and IV. Treatment with radiation alone offers the worst OS no matter the stage and should no longer be used as a solitary treatment modality.

Trends in treatment and overall survival among patients with proximal esophageal cancer.

BACKGROUND: The management of proximal esophageal cancer differs from that of tumors located in the mid and lower part of the esophagus due to the close vicinity of vital structures. Non-surgical treatment options like radiotherapy and definitive chemoradiation (CRT) have been implemented. The trends in (non-)surgical treatment and its impact on overall survival (OS) in patients with proximal esophageal cancer are unclear, related to its rare disease status. To optimize treatment strategies and counseling of patients with proximal esophageal cancer, it is therefore essential to gain more insight through real-life studies. AIM: To establish trends in treatment and OS in patients with proximal esophageal cancer. METHODS: In this population-based study, patients with proximal esophageal cancer diagnosed between 1989 and 2014 were identified in the Netherlands Cancer Registry. The proximal esophagus consists of the cervical esophagus and the upper thoracic section, extending to 24 cm from the incisors. Trends in radiotherapy, chemotherapy, and surgery, and OS were assessed. Analyses were stratified by presence of distant metastasis. Multivariable Cox proportional hazards regression analyses was performed to assess the effect of period of diagnosis on OS, adjusted for patient, tumor, and treatment characteristics. RESULTS: In total, 2783 patients were included. Over the study period, the use of radiotherapy, resection, and CRT in non-metastatic disease changed from 53%, 23%, and 1% in 1989-1994 to 21%, 9%, and 49% in 2010-2014, respectively. In metastatic disease, the use of chemotherapy and radiotherapy increased over time. Median OS of the total population increased from 7.3 mo [95% confidence interval (CI): 6.4-8.1] in 1989-1994 to 9.5 mo (95%CI: 8.1-10.8) in 2010-2014 (logrank P < 0.001). In non-metastatic disease, 5-year OS rates improved from 5% (95%CI: 3%-7%) in 1989-1994 to 13% (95%CI: 9%-17%) in 2010-2014 (logrank P < 0.001). Multivariable regression analysis demonstrated a significant treatment effect over time on survival. In metastatic disease, median OS was 3.8 mo (95%CI: 2.5-5.1) in 1989-1994, and 5.1 mo (95%CI: 4.3-5.9) in 2010-2014 (logrank P = 0.26). CONCLUSION: OS significantly improved in non-metastatic proximal esophageal cancer, likely to be associated with an increased use of CRT. Patterns in metastatic disease did not change significantly over time.

Combination of chemotherapy and radiotherapy: A thirty years evolution.

Chemoradiotherapy is now considered the standard of care for many locally advanced diseases. Cytotoxic drugs have been largely evaluated in this setting, with cisplatin and 5FU the most often used drugs. A large amount of pre-clinical studies has demonstrated the synergy between both modalities. Concomitant administration seems the more beneficial in many diseases. Emergence of new approaches, combining targeted therapies and radiotherapy (RT) is now a reality. The main example is the association of cetuximab and RT in head and neck carcinomas, even if, 14 years after the initial publication, the best way to use it is still unknown. New compounds as inhibitors of DNA-repair or immune checkpoints are under investigation and showed early promising results.

Improving CNS Delivery to Brain Metastases by Blood-Tumor Barrier Disruption.

Brain metastases encompass nearly 80% of all intracranial tumors. A late stage diagnosis confers a poor prognosis, with patients typically surviving less than 2 years. Poor survival can be equated to limited effective treatment modalities. One reason for the failure rates is the presence of the blood-brain barrier (BBB) and blood-tumor barrier (BTB) that limit the access of potentially effective chemotherapeutics to metastatic lesions. Strategies to overcome these barriers include new small molecule entities capable of crossing into the brain parenchyma, novel formulations of existing chemotherapies, and disruptive techniques. Here, we review BBB physiology and BTB pathophysiology. Additionally, we review the limitations of routinely practiced therapies and three current methods being explored for BBB/BTB disruption for improved delivery of chemotherapy to brain tumors.

Optimizing radiotherapy with immune checkpoint blockade in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fifth most common cancer, and its incidence is rapidly increasing in North America and Western Europe as well as South-East Asia. Patients with advanced stage HCC have very poor outcomes; therefore, the discovery of new innovative approaches is urgently needed. Cancer immunotherapy has become a game-changer and revolutionized cancer treatment. A comprehensive understanding of tumor-immune interactions led to the development of immune checkpoint inhibitors (ICIs) as new therapeutic tools, which have been used with great success. Targeting immune checkpoint molecules such as programmed cell death-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) reinvigorates anti-tumor immunity by restoring exhausted T cells. Despite their effectiveness in several types of cancer, of the many immune suppressive mechanisms limit the efficacy of ICI monotherapy. Radiation therapy (RT) is an essential local treatment modality for a broad range of malignancies, and it is currently gaining extensive attention as a promising combination partner with ICIs because of its ability to trigger immunogenic cell death. The efficacy of combination approaches using RT and ICIs has been well documented in numerous preclinical and clinical studies on various types of cancers but not HCC. The application of ICIs has now expanded to HCC, and RT is recognized as a promising modality in HCC. This review will highlight the current roles of PD-1 and CTLA-4 therapies and their combination with RT in the treatment of cancers, including HCC. In addition, this review will discuss the future perspectives of the combination of ICIs and RT in HCC treatment.

Cardiac Radiation Dose, Cardiac Disease, and Mortality in Patients With Lung Cancer.

BACKGROUND: Radiotherapy-associated cardiac toxicity studies in patients with locally advanced non-small cell lung cancer (NSCLC) have been limited by small sample size and nonvalidated cardiac endpoints. OBJECTIVES: The purpose of this analysis was to ascertain whether cardiac radiation dose is a predictor of major adverse cardiac events (MACE) and all-cause mortality (ACM). METHODS: This retrospective analysis included 748 consecutive locally advanced NSCLC patients treated with thoracic radiotherapy. Fine and Gray and Cox regressions were used to identify predictors for MACE and ACM, adjusting for lung cancer and cardiovascular prognostic factors, including pre-existing coronary heart disease (CHD). RESULTS: After a median follow-up of 20.4 months, 77 patients developed ≥1 MACE (2-year cumulative incidence, 5.8%; 95% confidence interval [CI]: 4.3% to 7.7%), and 533 died. Mean radiation dose delivered to the heart (mean heart dose) was associated with a significantly increased risk of MACE (adjusted hazard ratio [HR]: 1.05/Gy; 95% CI: 1.02 to 1.08/Gy; p < 0.001) and ACM (adjusted HR: 1.02/Gy; 95% CI: 1.00 to 1.03/Gy; p = 0.007). Mean heart dose (≥10 Gy vs. <10 Gy) was associated with a significantly increased risk of ACM in CHD-negative patients (178 vs. 118 deaths; HR: 1.34; 95% CI: 1.06 to 1.69; p = 0.014) with 2-year estimates of 52.2% (95% CI: 46.1% to 58.5%) versus 40.0% (95% CI: 33.5% to 47.4%); but not among CHD-positive patients (112 vs. 82 deaths; HR: 0.94; 95% CI: 0.70 to 1.25; p = 0.66) with 2-year estimates of 54.6% (95% CI: 46.8% to 62.7%) versus 50.8% (95% CI: 41.5% to 60.9%), respectively (p for interaction = 0.028). CONCLUSIONS: Despite the competing risk of cancer-specific death in locally advanced NSCLC patients, cardiac radiation dose exposure is a modifiable cardiac risk factor for MACE and ACM, supporting the need for early recognition and treatment of cardiovascular events and more stringent avoidance of high cardiac radiotherapy dose.

Trends in combined radio-chemotherapy for locally advanced rectal cancer: a survey among radiation oncology centers of Sicily region on behalf of AIRO.

AIM: To conduct a survey among Sicilian centers of radiation oncology belonging to Associazione Italiana di Radioterapia ed Oncologia Clinica (AIRO), to record the different methods of integration of radio-chemotherapy both in neoadjuvant and adjuvant settings, to evaluate surgical procedures in relation to the sphincter preservation and to report the different toxicity profiles of the treatment strategies. METHODS: A questionnaire was sent at the end of 2017 to all the radiation oncology centers of Sicily region in order to collect the data from individual centers and the treatment characteristics retrospectively over the previous 5 years, from 2012 to 2016. The required data were collected from 13 centers out of 17 which, in relation to the single catchment areas, correspond to approximately 85% of the Sicilian population. The requested data concerned the type of integrated treatment (neoadjuvant vs adjuvant vs radical), combination with chemotherapy (induction, concomitant, adjuvant), type of surgical intervention (sphincter-saving vs abdomino-perineal resection), disease stage, schedule and radiotherapy technique adopted, as well as toxicity detected over the treatment period. RESULTS: A total of 784 pts (M/F: 509/275) were treated between 2012 and 2016, with a median age of 67 years (range 25-92). The majority of patients was treated in the neoadjuvant phase (62% of the total) compared to the adjuvant phase (31%) and to those treated radically (7%). Twenty-five percent of patients did not receive combination chemotherapy mainly for cardiovascular problems. Chemotherapy used concomitantly to radiotherapy was single-agent capecitabine (73% of patients) or 5-fluorouracil (27%). The use of chemotherapy alone before concomitant treatment is more common for patients treated in the adjuvant phase (64% of this subgroup), while 14% of patients treated in the neoadjuvant phase received induction chemotherapy before the concomitant phase; in both cases of chemotherapy alone, the majority of patients (91%) received oxaliplatin-based protocols (FOLFOX/XELOX/CAPOX). Few patients (3%) received chemotherapy alone after the concomitant phase. Information on the surgical treatment received is available for 88% of the sample. Of these, 93% received a surgical treatment. The overall rate of sphincter-saving surgery (anterior resection) was 72%, but the contribution of neoadjuvant treatment allowed to reach a rate of 83% in this subgroup (against 65% found in the subgroup of patients treated in adjuvant phase). Traditional radiotherapy schedule (45-50 Gy in 25-28 fractions) was used in 90% of patients, of which an intensified treatment in neoadjuvant phase (45 Gy + boost of 9-10 Gy) was used in 11% of patients. A short-course regimen (25 Gy in 5 fraction) in neoadjuvant setting was opted rarely (7%). Three-dimensional conformal technique was preferred over intensity-modulated ones (73% vs 27%). Toxicity was mainly of grade I-II CTCAE (skin 23%, gastrointestinal 39%, genitourinary 14%) compared to grade III (gastrointestinal 4%, genitourinary and hematological < 1%). Interestingly, the toxicity rates were significantly higher in the adjuvant group compared to the neoadjuvant (GI: 58% vs 31%, GU: 21% vs 10%). CONCLUSION: The present survey shows that in the Sicily region integrated therapies for rectal cancer have allowed a neoadjuvant approach in the majority of patients, thus resulting in a greater use of sphincter conservative surgery. The toxicity has also been reported to be significantly less in this treatment setting.

Current clinical management of patients with glioblastoma.

BACKGROUND: Glioblastoma (GB) is the most aggressive primary brain tumor, historically resistant to treatment, and with overall fatal outcome. RECENT FINDINGS: Recently, several molecular subgroups and rare genetic alterations have been described in GB. In this review article, we will describe the current clinical management of patients with GB in the United States, discuss selected next-generation molecular-targeted therapies in GB, and present ongoing clinical trials for patients with GB. This review is intended for clinical and preclinical researchers who conduct work on GB and would like to understand more about the current standard of treatment of GB patients, historical perspectives, current challenges, and ongoing and upcoming clinical trials. CONCLUSIONS: GB is an extremely complex disease, and despite recent progress and advanced therapeutic strategies, the overall patient's prognosis remains dismal. Innovative strategies and integrative ways of approach to disease are urgently needed.