A Comparison Between Chemo-Radiotherapy Combined With Immunotherapy and Chemo-Radiotherapy Alone for the Treatment of Newly Diagnosed Glioblastoma: A Systematic Review and Meta-Analysis

Abstract

Background: Immunotherapy for GBM is an emerging field which is increasingly being investigated in combination with standard of care treatment options with variable reported success rates.

Objective: To perform a systematic review of the available data to evaluate the safety and efficacy of combining immunotherapy with standard of care chemo-radiotherapy following surgical resection for the treatment of newly diagnosed GBM.

Methods: A literature search was performed for published clinical trials evaluating immunotherapy for GBM from January 1, 2000, to October 1, 2020, in PubMed and Cochrane using PICOS/PRISMA/MOOSE guidelines. Only clinical trials with two arms (combined therapy vs. control therapy) were included. Outcomes were then pooled using weighted random effects model for meta-analysis and compared using the Wald-type test. Primary outcomes included 1-year overall survival (OS) and progression-free survival (PFS), secondary outcomes included severe adverse events (SAE) grade 3 or higher.

Results: Nine randomized phase II and/or III clinical trials were included in the analysis, totaling 1,239 patients. The meta-analysis revealed no statistically significant differences in group's 1-year OS [80.6% (95% CI: 68.6%-90.2%) vs. 72.6% (95% CI: 65.7%-78.9%), p = 0.15] or in 1-year PFS [37% (95% CI: 26.4%-48.2%) vs. 30.4% (95% CI: 25.4%-35.6%) p = 0.17] when the immunotherapy in combination with the standard of care group (combined therapy) was compared to the standard of care group alone (control). Severe adverse events grade 3 to 5 were more common in the immunotherapy and standard of care group than in the standard of care group (47.3%, 95% CI: 20.8-74.6%, vs 43.8%, 95% CI: 8.7-83.1, p = 0.81), but this effect also failed to reach statistical significance.

Conclusion: Our results suggests that immunotherapy can be safely combined with standard of care chemo-radiotherapy without significant increase in grade 3 to 5 SAE; however, there is no statistically significant increase in overall survival or progression free survival with the combination therapy.

Keywords: chemo-radiotherapy; glioma; high-grade glioma; immunotherapy; newly diagnosed glioblastoma; vaccine.

Figure 1

PRISMA diagram describing study design and selection (34).

Figure 2

Meta-analysis of 1-year OS in patients from all trials receiving standard of care or immunotherapy plus standard of care therapy. (A, B) 1-year OS forest and funnel plots of patients who received standard of care treatment [72.6% (95% CI: 65.7%–78.9%, I2: 71%)]. (C, D) 1-year OS forest and funnel plots of patients who received standard of care and immunotherapy treatment [80.6% (95% CI: 68.6%–90.2%, I2: 75%)] (p = 0.15). Funnel plots showing no significant publication bias found in the present meta-analysis in both groups with p-values of 0.89 and 0.72, in standard of care and immunotherapy treatment group respectively. In forest plots size of each square is proportional to its corresponding study’s total sample size. The ends of the horizontal bars denote a 95% CI. The diamond gives the overall odds ratio for the combined results of all trials. The center denotes the odds ratio, and the extremities denote the 95% CI.

Figure 3

Meta-analysis of 1-year OS in patients from trials receiving standard of care or cellular vaccine therapy plus standard of care therapy. (A, B) 1-year OS forest and funnel plots of patients who received standard of care treatment [71.2% (95% CI: 62.1–79.4, I² = 0%)]. (C, D) 1-year OS forest and funnel plots of patients who received standard of care and cellular vaccine treatment [76.5% (95% CI: 66.8%–85%, I² = 4%) (p = 0.21)]. Funnel plots showing no significant publication bias found in the present meta-analysis in both groups with p-values of 0.82 and 0.36, in standard of care and immunotherapy treatment group respectively. In forest plots size of each square is proportional to its corresponding study’s total sample size. The ends of the horizontal bars denote a 95% CI. The diamond gives the overall odds ratio for the combined results of all trials. The center denotes the odds ratio, and the extremities denote the 95% CI.

Figure 4

Meta-analysis of 1-year PFS in patients from all trials receiving standard of care or immunotherapy plus standard of care therapy. (A, B) 1-year PFS forest and funnel plots of patients who received standard of care treatment [30.4% (95% CI: 25.4–35.6; I² = 0%)]. (C, D) 1-year PFS forest and funnel plots of patients who received standard of care and immunotherapy treatment [37% (95% CI: 26.4–48.2, I² = 60%) (p = 0.17)]. Funnel plots showing no significant publication bias found in the present meta-analysis in both groups with p-values of 0.63 and 0.13 in standard of care and immunotherapy treatment group respectively. In forest plots size of each square is proportional to its corresponding study’s total sample size. The ends of the horizontal bars denote a 95% CI. The diamond gives the overall odds ratio for the combined results of all trials. The center denotes the odds ratio, and the extremities denote the 95% CI.

Figure 5

Meta-analysis of 1-year PFS in patients from trials receiving standard of care or cellular vaccine therapy plus standard of care. (A, B) 1-year PFS forest and funnel plots of patients who received standard of care treatment [26.2% (95% CI: 19.8–33.3, I² = 0%)]. (C, D) 1-year PFS forest and funnel plots of patients who received standard of care and cellular vaccine treatment [35% (95% CI: 18.2–53.9, I² = 62%) (p = 0.19)]. Funnel plots showing no significant publication bias found in the present meta-analysis in both groups p = 0.27 and p = 0.73, in standard of care and immunotherapy treatment group respectively. In forest plots size of each square is proportional to its corresponding study’s total sample size. The ends of the horizontal bars denote a 95% CI. The diamond gives the overall odds ratio for the combined results of all trials. The center denotes the odds ratio, and the extremities denote the 95% CI.

Figure 6

Meta-analysis of SAEs grade 3 to 5 in patients from trials receiving standard of care or immunotherapy plus standard of care therapy. (A, B) SAEs forest and funnel plots of patients who received standard of care treatment [43.8% (95% CI: 8.7–83.1, I² = 94%)]. (C, D) SAEs forest and funnel plots of patients who received standard of care and immunotherapy treatment [47.3% (95% CI: 20.8–74.6, I² = 95%) (p = 0.81)]. Funnel plots showing no significant publication bias found in the present meta-analysis in both groups p = 0.37 and p = 0.22, in standard of care and immunotherapy treatment group respectively. In forest plots size of each square is proportional to its corresponding study’s total sample size. The ends of the horizontal bars denote a 95% CI. The diamond gives the overall odds ratio for the combined results of all trials. The center denotes the odds ratio, and the extremities denote the 95% CI.

Figure 7

Meta-analysis of SAEs grade 3 to 5 in patients from trials receiving standard of care or cellular vaccine therapy plus standard of care. (A, B) SAEs forest and funnel plots of patients who received standard of care treatment [49.6% (95% CI: 0.2–99.8, I² = 94%)]. (C, D) SAEs forest and funnel plots of patients who received standard of care plus cellular vaccine treatment [57.3% (95% CI: 51.1–63.4, I² = 0%) (p = 0.68)]. Funnel plots showing no significant publication bias in both groups with p-values of 0.78 and 0.19 in standard of care and immunotherapy treatment group respectively. In forest plots size of each square is proportional to its corresponding study’s total sample size. The ends of the horizontal bars denote a 95% CI. The diamond gives the overall odds ratio for the combined results of all trials. The center denotes the odds ratio, and the extremities denote the 95% CI.