The Role of Radiation in the Treatment of Glioblastoma Multiforme

Here we are at the twentieth episode of the translation project of Ben Williams’ guide on treatment options for Glioblastoma Multiforme. This is chapter 14 of the guide. In this episode we talk about various forms of radiotherapy, proton therapy, hyperbaric oxygen and other radiosensitizers and radiotherapy with monoclonal antibodies. The advice is still to use this information to discuss it with the medical team that is following you, where you can also indicate references to supporting scientific works.

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For many years, the only treatment (other than surgery) offered to patients with glioblastomas was radiotherapy, since radiation was the only treatment that had proved useful in improving survival time in randomized clinical trials. This situation has continued in Europe until the last decade and chemotherapy (usually based on BCNU) has gradually been accepted as a useful additional treatment component despite the absence of definitive evidence from clinical trials. Part of the reason for accepting chemotherapy is that very few patients who had received radiation alone achieved a survival of more than two years (3-10%), compared with 15-25% of patients who also received chemotherapy.
The initial approach to the use of radiotherapy to treat gliomas was the radiation of the whole brain, but this approach was abandoned due to the significant neurological deficits that ensued even long after treatment. Current clinical practice uses a more focused radiation field that includes only 2-3 cm beyond the periphery of the tumor site. Due to the potential for radiation necrosis, the current radiation level considered safe is limited to 55-60 Gy. Even with this level of radiation, significant deficits can occur, often appearing several years after treatment. The most common causes of these deficits are damage to the myelin of the large white fibers, which are the main transmitters of information between different brain centers, and damage to small blood vessels, which results in inadequate blood supply to the brain. which also increases the likelihood of stroke. An additional risk, not yet clinically proven due to the short survival times typical of patients with glioblastoma, is the growth of secondary tumors due to radiation damage to DNA. However, experimental work with animal models has already shown that this risk is real (208). A group of three-year-old rhesus monkeys was subjected to radiation according to a protocol similar to the protocol used in human radiotherapy and was followed for a period between 2 and 9 years. An astonishing 82% of the monkeys developed glioblastoma during the follow-up period. It is currently unclear to what extent a similar risk occurs in long-term surviving human patients.

A secondary use of radiation in the treatment of gliomas is localized radiation in the tumor field, after treatment with external beam radiation has ended (or sometimes simultaneously), or through the use of implanted radiation sources (typically radioactive iodine). , according to a procedure known as brachytherapy, which through radiosurgery (gamma knife), or with the insertion into the tumor cavity of an inflatable balloon containing radioactive fluid (gliasite). These treatments are not used frequently now. Two different randomized brachytherapy trials failed to show a statistically significant survival benefit even though the procedure causes significant radiation necrosis toxicity (209). A recent radiosurgery study (210) also failed to demonstrate an advantage. The Gliasite has yet to be studied in a randomized study.
The interpretation of the failure to find a benefit in RCTs is that the initial studies indicating a survival benefit (usually by increasing survival time by approximately one year) involved a selected patient population that likely would have had a good prognosis regardless of the treatment received. However, the selection bias does not seem to be able to explain all the advantages of the procedure on its own. For example, the use of gliasite for recurrent GBM tumors produced a median survival time of 36 weeks (211), which compares favorably with the median survival time of only 28 weeks re-observed in the use of the gliadel wafer for recurrent tumors. with similar eligibility criteria. In addition, when patients received gliasite as part of initial treatment (212) and were then broken down based on prognostic variables and each partition compared to historical baseline data, survival time was better for patients. patients treated with the gliasite in each of the partitions.
Perhaps the best reported results regarding the enhancement of radiotherapy come from the combination of permanent radioactive iodine sources with wafer glia (212). Median survival for patients with recurrent glioblastomas was 69 weeks, although accompanied by considerable brain necrosis. The use of gliadel alone in the same treatment center, in comparison, produced a median survival time of 28 weeks, while the use of radioactive iodine sources alone produced a median survival of 47 weeks.
Impressive results were also obtained with the addition of fractional radiosurgery to the standard Stupp protocol for newly diagnosed patients (213). For 36 patients with GBM, the median survival (from diagnosis) was 28 months and the two-year survival was 57%. The median progression-free survival (from study entry) for patients with GBM was 10 months.
Previous results suggest that supplemental radiotherapy procedures provide some benefit, but it is important to understand that only a fraction of patients will be eligible for treatment. Radiation necrosis following treatment should also be considered.

Hyperbaric oxygen and other radiosensitizers

A potentially important modification of standard radiotherapy protocols involves the use of hyperbaric oxygen before each radiation session. In a study conducted in Japan (214), 57 patients with high-grade glioma received the standard radiation protocol with the addition of hyperbaric oxygen 15 minutes before each radiation session. Four rounds of chemotherapy were also administered, the first during the radiation treatment period. For the 39 patients with glioblastoma, the median survival time was 17 months, with a very high rate of tumor regression. For the 18 patients with anaplastic astrocytoma, the median survival was 113 months. Two-year survival was also measured by dividing the entire group of patients into recursive categories I-IV and V-VI, where the second included only patients with glioblastoma. For categories I-IV, the two-year survival was 50%; while for categories V and VI the two-year survival was 38%.
A long-standing goal of oncology with the use of radiation has been to find a radiation sensitizer that does not increase toxicity to healthy tissues. One of the most promising progress towards this goal was reported at the 2011 ASCO meeting (215). A new drug derived from the taxane family, with the name OPAXIO, was combined with the standard protocol with Temodar + radiation during the radiation treatment phase. The response rate for 25 patients (17 with GBM) was 45% with 27% achieving a complete response. At a median follow-up of 22 months, the median progression-free survival was 14.9 months (13.5 months for patients with GBM). Median overall survival was not included in the report. Note that the median PFS for standard treatment without OPAXIO is 6.9 months.

Proton radiation therapy

An alternative to standard X-ray radiation is the use of proton beams, although only a few treatment centers have the necessary equipment. To date, no significant comparison has been made between the effectiveness of proton beam radiation and the normal procedure. However, a recent study in Japan reported unusually positive results when the two forms of radiation were combined, the standard procedure in the morning and the proton beam radiation in the afternoon (216). In addition, the ACNU, a chemical cousin of the BCNU and the CCNU, was used concurrently. Median survival for the 20 patients was 21.6 months, with progression-free rates of 1 and 2 years of 45% and 16%. However, there were six cases of radiation necrosis that required surgery, indicating significantly higher toxicity than that normally occurs with the standard radiotherapy procedure.

Radiotherapy with monoclonal antibodies

An alternative to providing increased radiation beyond standard radiotherapy is to combine radioactive iodine-131 with a monoclonal antibody that targets a specific antigen, tenascin, which is present on almost all high-grade gliomas and not on normal brain cells. Monoclonal antibodies are infused directly into the tumor cavity over a period of several days and reportedly produce much less radiation necrosis than brachytherapy or radiosurgery. The median survival time found in a Phase 2 clinical trial using this treatment on recurrent GBM was 56 weeks (217). In a first study that used this approach as an initial treatment (218), patients received monoclonal antibodies, followed by standard radiotherapy and one year of chemotherapy. Of 33 patients, reoperation was required in only one case due to radiation necrotic tissue. Median survival time was 79 weeks for glioblastoma patients (27 of 33 patients in total) and 87 weeks for all patients. The estimated two-year survival rate for GBM patients was 35%. A subsequent outcome report for an extended number of patients indicated a median progression-free survival of 17.2 months, compared with 4-10 months for other treatment procedures (219). The median overall survival measured from the time of diagnosis was 24.9 months. At present, however, only one treatment center (Duke University) has used this procedure. A multicenter clinical trial has been planned, but the company sponsoring it has apparently shelved the plan and postponed it to a date to be defined.
A second type of monoclonal antibody treatment, developed at Hahneman University Medical School in Philadelphia, targets the epidermal growth factor receptor, which is overexpressed in most GBMs (220) For patients who have received this treatment in combination with standard radiotherapy, the median survival time was 14.5 months; For patients who received the same protocol but with the addition of temodar, the median survival was 20.4 months.
A third type of monoclonal antibody, called Cotara, is designed to bind to proteins that are exposed only when cells are dying, with the result that adjacent living cancer cells are irradiated by the radiation load carried by the monoclonal antibody. This rationale is based on the fact that GBMs exhibit considerable necrosis. This approach was developed by Peregrine Pharmaceuticals, a small biotech company with limited funding. The long-term outcomes of 28 patients with recurrent GBM followed for a period of nine years have recently been reported (221). Seven of the 28 patients survived more than a year, while 3 of the 28 survived more than five years (2 more than 9 years). Median survival was 38 weeks.


(208) Lonser, R. R., et al. Induction of glioblastoma multiforme in nonhuman primates after therapeutic doses of fractionated whole-brain radiation therapy. Journal of Neurosurgery, 2002, 97 (6), 1378-1389. 
(209) Vitaz, T. W., et al. Brachytherapy for brain tumors. J. of Neuro-Oncology, 2005, 73, 71-86. 
(210) Souhami, l. et al. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: Report of Radiation Therapy Oncology Group 93-05 protocol. Int. J. of Radiation Oncology, Biol Phys. 2004, 60(3), 853-860. (211) Welsh, J., et al. Gliasite brachytherapy boost as part of initial treatment of glioblastoma multiforme: a retrospective multi-institutional pilot study. Int. J. Radiat. Oncol. Biol. Phys. 2007, 89) 1): 159-165. 
(212) Darakchiev, B. J., et al. Safety and efficacy of permanent iodine-125 seed implants and carmustine wafers in patients with recurrent glioblastoma multiforme. J. Neurosurg, 2008, 108 (2), 236-242. 
(213) Balducci, Apicella, G., Manfrida, S., et al. Single-arm phase II study of conformal radiation therapy and temozolomide plus fractionated stereotactic conformal boost in high-grade gliomas: final report. Strahlenther. Onkol., 2010, 186(10), 558-64. 
(214 Ogawa, K. et al. Phase II trial of radiotherapy after hyperbaric oxygenation with multi-agent chemotherapy (procarbazine, nimustine. And vincristine) for high-grade gliomas: Long-term results. International J. Rad. Oncol. Biol. Phys., 2011, 82 (2), pp. 732-38. 
(215) Jeyaapalan, S. A., Goldman, M., Donahue, J., et al. Treatment with Opaxio (paclitaxel Poligluex), temozolomide and radiotherapy results in encouraging progression free survival in patients with high grade malignant brain tumor. 2011 ASCO meeting, Abstract #2036. 
(216) Mizumoto, M., et al. Phase I/II trial of hyperfractionated concomitant boost proton radiotherapy for supratentorial glioblastoma multiforme. Int. J. Radiat. Oncol. Biol. Phys. 2009, Aug. 19 epub ahead of print. 
(217) Cokgor, G. et al. Results of a Phase II trial in the treatment of recurrent patients with brain tumors treated with Iodine 131 anti-tenascin monoclonal antibody 81C6 via surgically created resection cavities. Proceedings of the American Society of Clinical Oncology, 2000, Abstract 628. 
(218) Reardon, D. A., et al. Phase II trial of murine (131) I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. Journal of Clinical Oncology, 2002, Vol. 20, 1389-1397. 
(219) Reardon, D., et al. An update on the effects of the effects of neuradiab on patients with newly diagnosed glioblastoma multiforme (GBM). Proceedings of the 2008 meeting of the Society for Neuro-Oncology, Abstract #MA-104. 
(220) Li, L., et al. Glioblastoma multiforme: A 20-year experience using radioimmunotherapy and temozolomide. Proceedings of the 2008 meeting of the Society for Neuro-Oncology, Abstract # IM-26. 
(221) Peregrine Pharmaceutical Press Release. Feb. 2, 2010: New Scientific Publication Highlights Long-Term Survival of Brain Cancer Patients Treated with Peregrine Pharmaceuticals’ Cotara ®.

Well! I hope you enjoyed reading, I was as faithful as possible. Very soon the last chapter! Only one is missing and then the translation of the guide will finally be complete.