Review |
Corresponding author: Alexandrina S. Nikova ( nikovaalex@gmail.com ) © 2022 Alexandrina S. Nikova, Georgios Sioutas, Michael Karanikas, Theodossios Birbilis.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Nikova AS, Sioutas G, Karanikas M, Birbilis T (2022) “Security dilemma”: active immunotherapy before versus after radiation therapy alone or chemo-radiotherapy for newly diagnosed glioblastoma. Folia Medica 64(2): 195-201. https://doi.org/10.3897/folmed.64.e62981
|
Management of glioblastoma should be aggressive and personalised to increase the quality of life. Many new therapies, such as active immunotherapy, increase the overall survival, yet they result in complications which render the search for the optimal treatment stra-tegy challenging.
In order to answer whether the available treatment options should be administered in a specific row, we performed a literature search and meta-analysis. The results show that overall survival among the different treatment groups was equal, while the rates of complications were unequal. After surgery, when active immunotherapy was administered before radiation, radiation and chemotherapy, complication rates were lower.
For newly diagnosed glioblastoma in adults, applying active immunotherapy after total resection but before the other complementary treatment options is associated with lower complication rates.
cancer, glioblastoma, immunotherapy, oncology
Glioblastoma is one of the most malignant tumours of the central nervous system (CNS), with a frequency rate between 3 and 5 cases per 100 000 population.[
Current investigations and approaches include immunotherapy in the standard therapeutic plan, which aims to activate the immune system, leading to a better median OS. Among the available types of immunotherapy, active immunotherapy (AI) effectively stimulates the immune system of the patients, thus producing immune cells targeting the tumour. Different protocols of active immunotherapy, in addition to radiation and chemotherapy, have been described.
Until now, however, there are a limited number of studies attempting to combine data with different glioblastoma treatment strategies, including AI, and their effects on outcomes. Therefore, the main goal of this study was to explore how AI affects OS and the rates of complications when each treatment protocol is compared to one another. Additionally, although AI, RT, and chemotherapy help increase the patients’ OS, all of them are linked to cytokine release, which represents a leading factor of post-therapeutic complications. This interplay describes the second topic of the current study.
We aim to study if the sequence of the administered treatment options for glioblastoma may affect the expected results after treatment. We will further try to hypothetically associate the possible differences found with the role of cytokines. This is based on the fact that, after active immunotherapy, extensive secretion of cytokines is related to complications, including neuronal damage, damage to the blood-brain barrier (BBB), DNA, and liver, among others.[
In order to investigate our initial hypothesis, we systematically searched for data on complications and OS after active immune therapy with radiation and chemotherapy in different combinations. We searched Medline, Cochrane, Wiley, and EMBASE databases for articles published between 2001 and 2018. Two independent authors conducted the literature search, using the following MeSH terms and keywords: active immunotherapy, glioblastoma, radiation therapy, chemotherapy, and cytokines. The search was further enhanced by hand-searching the reference lists of the included studies for further eligible studies (the snowball method).
The inclusion criteria were: human studies; articles in English; articles reporting newly diagnosed glioblastoma; articles reporting the OS and complication rates; articles reporting only active immunotherapy in addition to radiation therapy alone or in addition to chemo-and radiation therapy; patients over 18 years of age and articles reporting a concrete row of administered therapies (for instance: Surgery – Vaccination – Radiation Therapy or Surgery – Radiation + Chemotherapy – Vaccination); patients with gross total resection according to the surgical report; clinical studies; clinical trials; and case series.
The exclusion criteria were: non-human studies; articles in other than the English language; recurrent glioblastoma; pediatric patients; articles reporting other types of immunotherapy; case reports; reviews; comments; letters to the editor; articles with insufficient data on the OS or complication rates.
Data from the included studies were extracted independently by 2 reviewers, and disagreements were discussed with a third author. This way, the possible biases of the analysis were reduced, including measurement bias. The collected data was analysed using the statistical program J.A.S.P. (Jeffreys’s Amazing Statistics Program) 0.8.5.1. and SPSS version 25.
Our literature search identified 470 records. After titles and abstract screening, 97 studies were reviewed in full-text. Finally, 16 of them[
Depending on the sequence of the therapeutic options used, the included articles were divided into four groups:
1. Surgery (S), then Active immunotherapy (AI), then Radiation therapy (RT) alone.
2. S, then AI, then Radiation with chemotherapy (RTC).
3. S, then RT, then AI.
4. S, then RTC, then AI.
First, we performed an independent t-test on the OS (Table
Additionally, we performed Bayesian paired t-test for the complication rates, where only the combination 2 (S-AI-RTC) vs. 3 (S-RT-AI) appeared equal, while the rest of the combinations were unequal (Fig.
As mentioned, all treatment options can increase cytokine levels, which can result in complications. Irradiation may play a role in lowering cytokine levels shortly after its administration, and this may account for the low levels of complications if RT is prescribed alone after AI. On the other hand, the complications are expectedly high when RT and Chemotherapy are prescribed before AI, since all these treatment options cumulatively increase cytokine levels (Fig.
Study authors | OS months | Age years |
Sakamoto et al.[8] | 16.5 | 52 |
Muragaki et al.[9] | 19.8 | 47.13 |
Sampson et al.[10] | 26 | 52 |
Yu et al.[11] | 14.79 | 54.43 |
Steiner et al.[12] | 29.06 | 53 |
Chang et al.[13] | 15 | 58.57 |
Study authors | OS months | Age years |
Phuphanich et al.[14] | 38.4 | 52 |
Vik-Mo et al.[15] | 25.57 | 55 |
Chiocca et al.[16] | 15.64 | 58.6 |
Ardon et al.[17] | 18.3 | 57 |
Cho et al.[18] | 15.42 | 61.42 |
Hashimoto et al.[19] | 28 | 49 |
Ji et al.[20] | 42.3 | 52 |
Pellegatta et al.[21] | 20.1 | 54.08 |
Heimberger et al.[22] | 30 | 51 |
Sampson et al.[23] | 28.27 | 43.75 |
t | df | p-value two tailed | ||
OS V2 | OS V1 | -2.190 | 8.431 | 0.058 |
OS V2 only | OS V1 only | -2.777 | 3.008 | 0.069 |
OS V1 | OS V1 only | -2.141 | 2.009 | 0.165 |
OS V2 only | OS V2 | -1.268 | 9.106 | 0.236 |
Finally, correlation analysis was performed comparing the examined parameters (OS, age, and complication rate). According to the results, illustrated in Table
Glioblastoma is an aggressive neoplasm[
AI uses different antigens, including tumour parts, protein lysates, or mRNA from the neoplasm, synthetic peptides, and peptides from the MHC class I.[
In general, AI leads to a significant result when applied to smaller tumours.[
Overall, the complication symptomatology of all four groups analysed is comparable to that of CRS. Our analysis found that active immunotherapy alone appears to increase the OS of the patients; but in combination with the standard radio- and chemotherapy, it results in high rates of complications. A probable suggestion as a solution to this problem might be the application of AI before the gold standard therapy. This way, the levels of the cytokines could be maintained low, allowing the patients to take the chance of a better survival rate. As a result, lower complication rates can probably be translated to a better quality of life and lower costs of post-therapeutic management.
Readers should consider the weaknesses of this article when applying its results. Complications included in the analysis vary in terms of seriousness, and each study uses different definitions. Another limitation for generalizations is the heterogeneity of AI and chemotherapy types, as well as RT doses included in this study. Our hypothesis about the effect of cytokines on the different rates of complications is theoretical, and further studies are needed to investigate their actual role.
In order to reduce the possibility of measurement, selection, and confirmation bias, we included all the articles that agree with the inclusion criteria, regardless of their clinical outcome. Possible sample bias was reduced by excluding case reports. However, possible bias may stem from the fact that the included studies are based only on the English language and that no unpublished reports were included. Moreover, channelling bias may stem from the age groups included.
Active immunotherapy can result in lower complication rates if applied after total resection but before radiation or/and chemotherapy for newly diagnosed glioblastoma in adults. This treatment plan, although it does not affect OS, appears safer in terms of complications. Also, cytokines may play a leading role in complication rates. However, this is an observation and hypothesis; thus, further research is needed in order to find the best possible treatment protocol and minimize complication rates.
No conflicts of interest to declare.
No funding received.
This article does not contain any studies with human participants performed by any of the authors.