Introduction: Glioblastoma is a highly aggressive brain cancer with poor prognosis. Recurrence is common, and survival post-recurrence is limited. Identifying prognostic factors for recurrent glioblastoma can optimize treatment and improve outcomes.

Aim: This systematic review analyzed the clinical, molecular, and treatment-related variables that influence survival in patients with recurrent glioblastoma.

Materials and methods: A comprehensive search of PubMed, Scopus, and ProQuest databases included studies from the past decade, assessed using the Newcastle-Ottawa Scale (NOS).

Results: Sixteen studies were analyzed, highlighting age, Karnofsky Performance Status (KPS), molecular markers (MGMT promoter methylation, IDH mutations, TERT promoter mutations, TP53 alterations, ATRX loss, and Ki-67 expression), and surgical resection extent as key prognostic factors. Younger patients with higher KPS scores and favorable molecular markers had better survival. Molecular profiling and maximal resection correlated with improved overall survival (OS). Salvage therapies like chemotherapy and re-resection provided marginal benefits, with variability based on patient demographics and tumor genetics.

Conclusion: Age, KPS, molecular markers, and surgical resection extent significantly predict survival in recurrent glioblastoma. The review underscores the importance of molecular profiling for personalized treatment, though current salvage therapies show limited effectiveness. Innovative approaches are needed to enhance outcomes for this aggressive disease.

Abbreviations used in the article: BSC: best supportive care; CRE: complete resection of enhancing tumor; DFS: disease-free survival; GBM: glioblastoma; GTR: gross total resection; KPS: Karnofsky Performance Status; NOS: Newcastle-Ottawa Scale; OS: overall survival; PFS: progression-free survival; rGBM: recurrent glioblastoma multiforme; RTOG–RPA: Radiation Therapy Oncology Group – Recursive Partitioning Analysis; TTF: tumor-treating fields

glioblastoma, recurrent glioblastoma, prognostic factors, survival, molecular markers

Glioblastoma is one of the most aggressive and lethal forms of brain cancer and is characterized by rapid proliferation and invasive behavior. Despite advances in medical treatments, the prognosis for patients diagnosed with glioblastoma is dismal, with a median survival of 12 to 15 months.‌^[1] Even with surgery, radiation therapy, and chemotherapy, recurrence is nearly inevitable, further complicating disease management. The challenge of recurrent glioblastoma highlights the urgent need to identify factors that can improve patient outcomes and guide personalized treatment strategies.^[2]

Recurrent glioblastoma refers to the return of the tumor after the initial therapy and often exhibits greater resistance to standard treatments. By identifying these factors, clinicians can tailor their therapeutic approaches to enhance patient survival and quality of life.^[1] Several prognostic variables have been proposed in the context of recurrent glioblastoma, including patient demographics (age), Karnofsky Performance Status (KPS), tumor genetics (MGMT promoter methylation, IDH mutations), extent of resection, response to salvage therapies, and the time between initial treatment and recurrence (progression-free survival). Each of these factors plays a critical role in determining patient outcomes and in guiding treatment decisions.^[2]

Prognostic variables play a crucial role in assessing outcomes for patients with recurrent glioblastoma. Patient demographics, particularly age, are significant, as younger individuals generally exhibit better survival outcomes. Karnofsky Performance Status (KPS) is another critical factor, with higher scores correlating with improved prognosis and better tolerance of salvage therapies.^[3] Additionally, tumor genetics, such as MGMT promoter methylation and IDH mutations, have been extensively studied. MGMT methylation is associated with a more favorable response to alkylating agents like temozolomide, whereas IDH mutations are indicative of a better overall prognosis, despite being less common in recurrent GBM cases.^[4,5] Tumor proliferation markers, such as Ki-67, further refine prognosis, as higher Ki-67 labeling indices are associated with increased tumor aggressiveness and lower survival rates.^[6] Additionally, TERT promoter mutations are linked to worse prognosis and more aggressive tumor phenotypes, often in combination with ATRX and TP53 mutations, which further impact tumor biology and therapeutic resistance.^[7]

The extent of resection at the time of recurrence significantly influences survival outcomes, with maximum resection typically leading to longer progression-free and overall survival compared to subtotal resection.^[8] However, repeated surgical interventions must be weighed against potential morbidity. Additionally, the response to salvage therapies, including re-irradiation, bevacizumab, and targeted molecular therapies, varies among patients based on genetic and clinical factors. Studies indicate that MGMT-methylated and IDH-mutant tumors respond better to salvage treatments, further underlining the importance of genetic profiling in treatment selection.^[9]

Another essential prognostic factor is the time between initial treatment and recurrence, also known as progression-free survival (PFS). A longer PFS before recurrence often suggests a more indolent tumor biology and better response to subsequent therapies.^[10] In contrast, patients with early recurrence tend to have a more aggressive disease course and poorer survival outcomes. Given the complex interplay of these variables, personalized treatment approaches incorporating patient-specific genetic and clinical characteristics are essential to optimizing outcomes for recurrent GBM patients.^[11]

In summary, recurrent glioblastoma presents a formidable challenge in terms of both prognosis and treatment. Understanding the complex interplay between clinical, molecular, and therapeutic factors is essential to improve patient outcomes and guide treatment decisions. Although significant progress has been made, more research is needed to clarify these relationships and to develop personalized and effective treatment strategies. Ongoing advancements in molecular profiling and the development of novel therapies offer hope for the better management of this devastating disease.

Recurrent glioblastoma (GBM) presents a formidable challenge in terms of prognosis and survival as evidenced by its persistent resistance to conventional therapies. A systematic analysis identified several crucial prognostic factors that significantly affect patient outcomes, including age, extent of surgical resection, molecular markers, and progression-free survival. Age has emerged as a critical determinant, with younger patients generally exhibiting more favorable treatment responses, potentially due to their enhanced ability to withstand aggressive interventions. In contrast, older individuals (classified as those aged 65 and above) often face limited treatment options, primarily because of age-related health complications and reduced tolerance for intensive therapeutic approaches.

The degree of surgical tumor removal consistently correlates with improved survival rates, with maximal resection offering distinct advantages. However, the tumor location and complexity frequently constrain the feasibility of extensive surgical interventions, limiting the potential for aggressive surgical strategies.

Molecular markers such as IDH1 mutations and MGMT promoter methylation have emerged as significant prognostic factors, providing insights into tumor behavior and guiding personalized treatment strategies. These markers not only aid in predicting treatment response but also open up the potential for more targeted therapies. Beyond MGMT and IDH, other molecular markers, including TERT promoter mutations, TP53, ATRX loss, and Ki-67, have also been identified as key prognostic indicators in recurrent GBM and will be discussed in this review. This review also highlights PFS and salvage therapies as critical elements in recurrent GBM management. A longer PFS generally suggests a less aggressive tumor and better outcomes with subsequent therapies, while the effectiveness of salvage treatments such as re-irradiation, chemotherapy, and novel approaches such as tumor-treating fields (TTF) or immunotherapy depends largely on factors such as the patient’s performance status and tumor molecular characteristics.

Additionally, this review emphasizes the importance of clinical trials in exploring emerging therapies, such as gene therapy and immunotherapy, which show promise in improving outcomes. Beyond survival, the discussion highlights the need for a holistic approach that integrates palliative care and measures to improve the quality of life. Managing recurrent glioblastoma requires addressing not only survival but also the broader physical and emotional needs of patients as they navigate this aggressive and challenging disease. The studies summarized in Table 1 collectively highlight the significant factors that influence survival in patients with recurrent glioblastoma. Common prognostic factors identified across these studies include age, Karnofsky Performance Status, tumor grade, extent of surgical resection, and molecular markers such as MGMT promoter methylation and IDH mutations. These factors play a crucial role in determining treatment response and overall survival (OS), underlining the complexity of managing recurrent glioblastoma. Research has consistently highlighted the need for individualized treatment plans tailored to both clinical and genetic factors.

Age and KPS score have emerged as the most consistent predictors of survival in multiple studies. Fu et al.^[2] demonstrated that younger patients with higher KPS scores tended to have better outcomes, a finding echoed by Wong et al.^[32], who also emphasized the role of tumor histology in shaping prognosis. Similarly, Van Linde et al. found that age and KPS significantly influenced the efficacy of treatments, such as re-resection and systemic therapies. These findings reinforce the importance of evaluating patient demographics and performance status to effectively guide treatment decisions. Understanding these variables allows clinicians to make more informed choices regarding surgical intervention, chemotherapy, or supportive care, maximizing the potential for extended survival and quality of life. A study by Kim et al.^[22] also stated that an older population older than 65 years of age increases the incidence of glioblastoma. Immunological factors associated with aging, GBM progression, and/or resistance to treatment.

Molecular and genetic markers play critical roles in the management of recurrent glioblastomas. Studies by Fu et al. and Brown et al. underlined the significance of MGMT promoter methylation and IDH mutations as key prognostic markers. Patients with MGMT methylation generally showed a better response to chemoradiotherapy and longer survival outcomes. For instance, Fu et al. used MGMT methylation in combination with tumor grade and gliosis percentage to stratify patients into high- and low-risk groups, thereby improving the precision of treatment approaches. These molecular markers are becoming increasingly relevant in designing personalized therapies, as they help identify patients who might benefit from targeted treatments or clinical trials exploring innovative therapies such as immunotherapy or gene therapy.

Recurrent GBM is driven by key molecular alterations, including telomerase reverse transcriptase (TERT) promoter mutations, TP53 and ATRX mutations, and Ki-67 expression. TERT promoter mutations are frequently observed in GBM and are associated with aggressive tumor behavior, poor prognosis, and increased recurrence risk.‌^[23] TP53 mutations, commonly found in secondary GBM, disrupt tumor suppressor functions and promote genetic instability.^[24] ATRX mutations are linked to the alternative lengthening of telomeres (ALT) pathway, influencing tumor proliferation and therapy resistance.^[25] Additionally, Ki-67, a marker of cellular proliferation, is correlated with increased tumor aggressiveness and recurrence rates, making it a potential prognostic biomarker.^[26] These molecular factors collectively contribute to GBM recurrence, influencing treatment responses and patient survival outcomes.

The challenge of managing recurrent glioblastomas is particularly evident in studies focusing on salvage therapies. Van Linde et al. highlighted the limited effectiveness of current salvage treatments, with the median survival rates remaining modest despite aggressive intervention. Wong et al. found that chemotherapy regimens offered only slight improvements in progression-free survival (PFS), whereas Van Linde’s analysis demonstrated that even re-resection and systemic therapies yielded only marginal survival benefits. This reflects the overall resistance of recurrent glioblastomas to treatment, necessitating innovative approaches for managing tumor recurrence.^[12]

Repeat surgery plays a crucial role in recurrent glioblastoma management, and meta-analyses have highlighted its impact on survival. Lu et al. in World Neurosurgery reviewed multiple studies and concluded that repeat surgery significantly improves overall survival, particularly in patients with good preoperative Karnofsky Performance Status and favorable molecular markers.^[27] Gross total resection (GTR) of recurrent glioblastoma is associated with significantly improved progression-free survival compared to subtotal resection, as highlighted in a systematic review by Han et al.^[28] Similarly, Jackson et al.^[29] found that patients undergoing GTR had longer PFS than those with STR or biopsies, reinforcing the importance of maximal tumor resection for better outcomes. Lu et al.^[30], also in World Neurosurgery, reinforced the importance of extent of resection, demonstrating that achieving maximal cytoreduction correlates with longer survival, particularly when combined with adjuvant therapies.^[30]

Re-irradiation has emerged as a viable salvage option, particularly for patients ineligible for surgery. Kazmi et al., in the Journal of Neuro-Oncology, analyzed multiple re-irradiation studies and found that fractionated stereotactic radiotherapy offers better local control and survival benefits while minimizing toxicity.^[31] More recently, Luo et al. in Clinical Neurology and Neurosurgery confirmed that hypofractionated re-irradiation, especially when combined with systemic therapies such as bevacizumab, improves survival outcomes while reducing treatment-related adverse effects.^[32] Bevacizumab, an anti-VEGF monoclonal antibody, has been extensively studied as a salvage therapy, often used in combination with chemotherapy. While it provides symptomatic relief and prolongs PFS, meta-analyses suggest its impact on overall survival remains limited.

Moreover, the timing and type of intervention significantly affected patient outcomes. Van Linde et al. showed that patients who underwent re-resection experienced longer survival than those who only received supportive care, indicating the potential value of surgery in select cases. However, the feasibility of aggressive interventions such as surgery is often limited by factors such as tumor location and patient performance status. For instance, Audureau et al. emphasized the importance of KPS at the time of progression as a key determinant of overall survival.^[13] Patients with higher KPS scores were more likely to tolerate surgery and chemotherapy, leading to better outcomes than those with poorer performance status.

The complexity of glioblastoma recurrence management is further compounded by the inherent resistance of tumors to conventional therapies. Schaub et al. and Brown et al. highlighted the role of advanced therapies such as bevacizumab in extending survival.^[15,21] Schaub et al. reported that bevacizumab, either alone or in combination with irinotecan, was associated with improved survival, particularly in patients who had already undergone multiple lines of chemotherapy. Similarly, Brown et al. emphasized the importance of combining debulking surgery with chemoradiotherapy in patients with favorable molecular profiles, such as MGMT promoter methylation, to maximize treatment efficacy.^[15,21]

The recurrence patterns and molecular characteristics of glioblastomas also play pivotal roles in determining patient survival. Karschnia et al.^[19] showed that patients who underwent maximal resection of contrast-enhancing tumor volume had significantly longer survival than those with residual tumors.^[19] This is consistent with broader research on the importance of surgical intervention in glioblastoma management, particularly when combined with postoperative chemoradiation. Additionally, patients with molecular markers, such as IDH mutations or MGMT methylation, are more likely to benefit from aggressive surgical approaches, further emphasizing the importance of personalized treatment strategies based on both clinical and genetic factors.

As illustrated by Vaz-Salgado et al., age remains a critical factor in determining the success of treatment interventions. Older patients generally exhibit lower survival rates due to comorbidities and reduced tolerance to aggressive therapies. This is particularly evident in studies focusing on bevacizumab and other immunotherapies, where younger patients with a good performance status tend to derive greater benefits from these treatments. Vaz-Salgado et al. also highlighted the complexity of managing recurrent glioblastoma in older populations, as these patients often require more conservative treatment approaches, balancing the quality of life with potential survival benefits.^[16]

The importance of molecular profiling in determining treatment outcomes is further highlighted in studies by Fekete et al. They demonstrated that patients with hypermethylated MGMT and a better performance status showed significantly longer survival than those without these genetic markers. These findings underscore the growing role of precision medicine in recurrent glioblastoma, where personalized treatment plans based on molecular characteristics offer the best chance of improving patient outcomes. The integration of genetic testing into routine clinical practice is becoming increasingly important for guiding treatment decisions in this patient population.^[17]

Additionally, the extent of surgical resection continues to be a crucial factor in determining patient survival. Studies by Blakstad et al.^[20] emphasized the survival benefits of gross total resection (GTR) compared with partial or no resection. Blakstad et al. found that patients who underwent GTR had significantly longer survival, particularly those with MGMT methylation, and younger age. This finding supports the notion that maximal safe resection, when feasible, should be considered in the management of recurrent glioblastoma to optimize the survival outcomes.^[20]

In contrast, the role of supportive care in patients with a poor performance status or advanced disease has been highlighted in several studies. Van Linde et al. and Audureau et al. noted that, for patients with low KPS scores, aggressive interventions may not be appropriate because of the risks and limited benefits. Instead, the best supportive care (BSC) focuses on symptom management and quality of life. These studies underscore the importance of individualized care plans that consider both patients’ overall health and likelihood of treatment success.^[12,13]

The overall prognosis for recurrent glioblastoma remains poor, as reflected in the studies highlighting the aggressive nature of this tumor and the limited effectiveness of current treatment strategies. Despite advances in surgical techniques, radiotherapy, and chemotherapy, recurrent glioblastomas remain incurable. The prognosis remains dismal, with median overall survival post-recurrence ranging between 6 to 10 months.^[6]

This systematic review highlights the complex management of recurrent glioblastoma, emphasizing critical prognostic factors such as age, KPS, tumor grade, molecular markers, and resection extent. Advances in neuro-oncology, including molecular profiling and personalized treatments, have shown promise for better survival and quality of life. Nonetheless, optimizing salvage therapies, managing recurrences, and overcoming treatment resistance remain significant challenges that necessitate ongoing research and innovation.

Studies on recurrent glioblastoma often face limitations in study design, sample size, and treatment protocols, which complicate direct comparisons. Jilla et al. had small sample sizes, which limits generalizability. The retrospective nature of most studies introduces a bias in patient selection and data collection. Variations in treatment modalities and salvage therapies across institutions further complicate the interpretation of the survival outcomes. Although molecular markers, such as MGMT methylation, are crucial, not all patients undergo genetic profiling, limiting personalized treatment applicability. Additionally, varying follow-up periods, with some lacking long-term data, hinder the assessment of the impact of treatment on overall survival and disease progression.

The prognosis and survival outcomes of patients with recurrent glioblastoma remain poor despite advancements in surgery, chemotherapy, and radiotherapy. Key prognostic factors identified included age, Karnofsky Performance Status (KPS), molecular markers such as MGMT promoter methylation, and the extent of surgical resection. Younger patients and those with higher KPS scores showed better survival outcomes, with molecular markers increasingly guiding personalized treatment. The limited efficacy of salvage therapies and the resistance of tumors to conventional treatments underscores the need for ongoing research and innovative therapies. Advances in neuro-oncology, including molecular profiling and individualized treatments, offer the best hope for improving the survival and quality of life of patients with this aggressive disease.

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The authors declare that they have no conflict of interest and no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript. 

R.A.A., F.D., and I.R.A contributed to the design and implementation of the research; R.A.A., A.R.L, and I.R.A - to the analysis of the results and to the writing of the manuscript; R.A.A. conceived the original and supervised the project.