Source of Research Article: Cao C, Wang L, Jiang F, et al. Granulocyte-macrophage colony-stimulating factor for newly diagnosed glioblastoma. Neoplasia. 2025; 47:101156.
Recently, the research team led by Professor Chen Xiaozhong and Professor Cao Canneng from Zhejiang Cancer Hospital published their latest research findings on radiotherapy and chemotherapy combined with GM-CSF. Their treatment regimen for glioblastoma has achieved significant clinical effects, providing a viable new treatment option for patients with this type of tumor. Glioblastoma (GBM) is the most common malignant brain tumor in adults, with an extremely poor prognosis. Despite a deeper understanding of the molecular biology of GBM in recent decades, treatment progress remains slow, and patient survival has not been significantly prolonged. Currently, the treatment regimen for newly diagnosed GBM is still based on the “Stupp protocol” established in 2005, which involves surgical resection of the tumor followed by concurrent chemoradiotherapy (radiotherapy combined with temozolomide, TMZ), and subsequent adjuvant TMZ chemotherapy.
Current Status of Glioblastoma Treatment Background
Since its establishment, the Stupp protocol has been the cornerstone of treatment for newly diagnosed GBM. This protocol improved the median survival of patients to approximately 14.6 months and the 2-year survival rate to about 27%, but the 5-year survival rate remains less than 10%. This indicates that even standard treatment can only extend patient survival to a limited extent, and GBM remains a highly lethal disease. In recent years, to further improve the treatment outcomes of GBM, researchers have actively explored the following aspects:
- Improvements in Radiotherapy Techniques: To improve tumor control rates while reducing damage to normal brain tissue, radiotherapy techniques are constantly advancing. Intensity-modulated radiotherapy (IMRT), compared to traditional three-dimensional conformal radiotherapy, can better achieve precise control of dose distribution, improving dose homogeneity in the target area while reducing the radiation dose to surrounding normal tissues. In addition, stereotactic radiosurgery (SRS) and stereotactic fractionated radiotherapy (SRT) and other techniques are also applied in specific situations to improve local control. In recent years, studies have explored hypofractionated radiotherapy and accelerated fractionation radiotherapy, aiming to enhance the biological effects of radiotherapy, but their clinical benefits still need further validation. Hypofractionated IMRT, used in this study, which involves delivering higher doses of radiation per fraction in a shorter overall treatment time, represents a significant advancement in radiotherapy techniques.
- Exploration of Chemotherapy Drugs: Temozolomide remains the first-line chemotherapy drug for GBM. However, the efficacy of single-drug chemotherapy is limited, and drug resistance is a major challenge. Researchers have attempted to use TMZ in combination with other chemotherapy drugs or explore new chemotherapy drugs, but so far, no other chemotherapy regimen has been shown to be significantly superior to TMZ.
- Attempts at Targeted Therapy: A series of targeted drugs have been developed targeting common molecular targets in GBM, such as EGFR and VEGF. However, clinical trial results have mostly been disappointing. For example, bevacizumab, an anti-angiogenic drug, although showing some efficacy in recurrent GBM, failed to prolong the survival of patients with newly diagnosed GBM. Other targeted drugs, such as EGFR inhibitors, have also failed to achieve breakthrough progress in GBM treatment.
- The Rise and Challenges of Immunotherapy: Immunotherapy has achieved revolutionary success in various tumors, and high hopes are placed on the GBM field. However, early immune checkpoint inhibitors (such as PD-1/PD-L1 antibodies) have encountered setbacks in clinical trials for GBM. Phase III clinical trials such as CheckMate-143, CheckMate-498, and CheckMate-548 have all failed to meet their primary endpoints. This may be related to the unique immunosuppressive microenvironment of GBM, including low tumor cell antigenicity, limitations of the blood-brain barrier, and the presence of a large number of immunosuppressive cells in the tumor microenvironment. Immunotherapy based on cytokines has become one of the important research directions in GBM immunotherapy in recent years.
- Exploration of Combined Treatment Strategies: Considering the complexity of GBM and the challenges of treatment, combined treatment strategies have become an important direction of research. Integrating multiple approaches such as radiotherapy, chemotherapy, and immunotherapy to achieve synergistic effects and overcome the limitations of single treatments is a potential way to improve the treatment outcomes of GBM. [Image]
Data Comparison Between Traditional Stupp Protocol and Chen Xiaozhong & Cao Canneng Team’s Regimen for Glioblastoma
| Data Comparison | Traditional Stupp Protocol | This Study’s Regimen |
|---|---|---|
| Radiotherapy Dose | 60Gy/30 fractions | 52.5Gy/15 fractions |
| Treatment Cycle | 6 weeks | 3 weeks |
| 6-month PFS | ~53.9% | 68.3%↑ |
| 2-year OS Rate | ~27.2% | 35.6%↑ |
| Core Innovation Point | Simple Chemoradiotherapy | Combined GM-CSF Immunomodulation |
Highlights of This Study
The highlight of this study lies in exploring the feasibility and safety of hypofractionated IMRT, temozolomide combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment of newly diagnosed GBM. GM-CSF is a potent cytokine that can promote the differentiation of myeloid cells and act as an immunostimulatory adjuvant, stimulating anti-tumor immune responses.
- Exploration of Hypofractionated Radiotherapy: Traditional GBM radiotherapy regimens are usually 60Gy in 30 fractions over 6 weeks. Hypofractionated radiotherapy uses a higher dose per fraction and shortens the treatment cycle, which theoretically may have certain biological advantages, while also improving patient treatment compliance, reducing medical visits, and lowering medical costs. The 15-fraction regimen used in this study (3.5Gy × 15F for high-risk areas, 3.0Gy × 15F for low-risk areas) significantly shortened the radiotherapy time while ensuring the target dose. Previous meta-analyses have also shown that hypofractionated radiotherapy may improve OS and PFS in GBM patients, suggesting the potential of hypofractionated radiotherapy in GBM treatment.
- Immunoadjuvant Effect of GM-CSF: GM-CSF, as an immunostimulant, can enhance T cell-mediated anti-tumor immune responses by promoting the maturation and activation of antigen-presenting cells (such as dendritic cells). In studies of other tumors, GM-CSF has been shown to enhance the efficacy of immunotherapy. For example, in unresectable or metastatic melanoma, ipilimumab combined with GM-CSF is more effective than ipilimumab alone. This study explores the addition of GM-CSF to concurrent chemoradiotherapy for GBM, aiming to utilize the immunoadjuvant effect of GM-CSF to enhance the anti-tumor effect of chemoradiotherapy.
- Safety and Feasibility of the Combined Treatment Regimen: Early studies suggested that the combined use of GM-CSF and concurrent chemoradiotherapy may lead to severe toxic reactions. However, the results of this study show that the regimen of hypofractionated IMRT, temozolomide combined with GM-CSF is safe and feasible. In the study, no grade 3 or 4 hematological toxicity was observed, and only 12.2% of patients discontinued GM-CSF due to GM-CSF-related toxicity (non-hematological toxicity). All patients completed radiotherapy and concurrent temozolomide chemotherapy as planned. This indicates that under modern radiotherapy technology (IMRT) and dose control, the safety of combining GM-CSF with concurrent chemoradiotherapy is acceptable.
- Preliminary Efficacy: The primary endpoint of this study was 6-month progression-free survival rate (PFS). The study results showed that the 6-month PFS rate was 68.3%, which reached the preset research hypothesis, indicating that this combined regimen may have certain efficacy. The median overall survival (OS) for patients was 16.7 months, the 1-year OS rate was 70.7%, and the 2-year OS rate was 35.6%. Compared with the survival data of simple chemoradiotherapy reported in previous literature, patient prognosis is improved.
- Biomarker Exploration: Researchers also explored changes in peripheral blood biomarkers before and after GM-CSF treatment. The results found that TNF-α and IL-18 levels increased after GM-CSF treatment, while the proportion of CD19-positive cells, IgG, and CXCL12 levels decreased. These changes suggest that GM-CSF may have a certain regulatory effect on the immune system, but the changes in these biomarkers were not statistically correlated with patient PFS and OS. Future research can further explore the immune mechanism of GM-CSF combination therapy and look for biomarkers that predict efficacy.
Limitations of This Study: Single-Arm Phase II Study: Lack of a control group, making it impossible to directly compare the efficacy difference between combined GM-CSF and simple chemoradiotherapy. Limited sample size: Only 41 patients were enrolled, and the sample size is relatively small, so the results may be affected by chance factors. Heterogeneity of patient population: Compared with prospective large-sample studies, the MGMT promoter methylation status and IDH1 mutation status of the patients included in the study are somewhat different, which may affect the interpretation of the results. Quality of Life Assessment: The study did not assess the quality of life of patients, and it is impossible to fully understand the impact of combined treatment on patients’ quality of life.
Despite these limitations, this study still provides new ideas and directions for the treatment of GBM. It initially confirmed that hypofractionated IMRT, temozolomide combined with GM-CSF for the treatment of newly diagnosed GBM is safe and feasible, and shows certain efficacy signals. Future large-scale, multi-center, randomized controlled Phase III clinical trials are needed to further verify the efficacy of this combined regimen and to deeply study its immune mechanism and biomarkers. With the support of modern radiotherapy technology, GM-CSF can be safely combined with concurrent chemoradiotherapy for the treatment of GBM and may bring certain clinical benefits. With the continuous development of immunotherapy in the field of oncology, GM-CSF, as a classic immunostimulant, is expected to play a greater role in the combined immunotherapy of GBM. In the future, combining GM-CSF with other immunotherapies such as immune checkpoint inhibitors may further improve the treatment effect of GBM and improve patient prognosis.
About the Principal Investigator
Professor Cao Canneng, Associate Chief Physician, Deputy Director of the Department of Nasopharyngeal Carcinoma/Head and Neck Radiotherapy at Zhejiang Cancer Hospital. He also serves as the Chairman of the Youth Committee of Nasopharyngeal Carcinoma of the Zhejiang Anti-Cancer Association, a member of the Nasopharyngeal Carcinoma Professional Committee of the Chinese Anti-Cancer Association, and many other academic positions. He has long been committed to clinical research on nasopharyngeal carcinoma and refractory head and neck malignancies. He specializes in radiotherapy and comprehensive treatment of nasopharyngeal carcinoma, head and neck tumors, and central nervous system tumors, and is dedicated to improving patient treatment efficacy and quality of life. As the first author, he has published more than 20 SCI papers, undertaken multiple research projects, co-edited monographs, and participated in the compilation of multiple guidelines. He has won the second prize of the Science and Technology Award of the Chinese Anti-Cancer Association.
