1. Traditional radiotherapy or proton therapy?

It seems that there is no universal or nonambiguous answer. The advantage of proton therapy is the chance of successful damage of the tumor without excessive radiation of healthy tissue, which is possible, among other factors, due to high precision: the optimal therapeutic dose is established for a given depth. In proton therapy, rays do not consist of small particles of light, i.e. photons, as is the case in traditional radiotherapy, but of charged nuclei of nitrogen atoms. The beam can be directed with high precision and at great speed. Proton therapy would be advantageous in the treatment of tumors localized at great depth or in the close neighborhood of nerve centers. However, if the tumor is localized in such a key center, for instance in the brainstem, the beam has to be directed at the critical place. Then the advantage of proton therapy seems less obvious, which does not imply lower effectiveness. Even if critical centers are exposed to radiation, the advantage can consist of smaller radiation doses directed at other parts of the brain (for instance, the optic nerve). This method is much younger than traditional radiotherapy, which explains why both the scholars and the doctors have less experience and less data concerning prolonged side effects. However, they are expected to be less serious than those caused by photon radiation. Before deciding one should talk to the doctor, asking about expected advantages. The decisive factor seems to be the localization of the tumor. We managed to arrange a consultation, granted free of charge, with a staff member of the Center of Proton Therapy in Oklahoma (https://www.procure.com/Oklahoma-Explore). Since he did not suggest that proton therapy might prove obviously advantageous (when treating the particular tumor in question), we decided to select traditional photon radiation therapy in Poland.

2. How much does proton therapy cost?

Payable radiation treatment is available in many European countries; quite experienced are clinics in Germany and the Czech Republic.
The Czech center is situated in Prague. The first step involves filling the form called “Make your appointment as soon as possible”; afterwards the patient undergoes further qualification procedures to be found on the homepage: http://proton-cancer-treatment.com/en/for-patients/

The cost is established following the preparation of an individual treatment scenario; it will amount to some tens of thousands of euros.

3. Other methods of radiation and their potential advantage over conventional radiotherapy
Carbon ion therapy

It is advisable to consider carbon ion therapy, which is a very modern method of treatment. Its characteristic feature is the weight of charged carbon ions, and their biological effectiveness may be higher than that of protons.

The Heidelberg clinic is one of the few world centers which offer this type of radiation, applicable to adult glioblastoma patients. The first step consists in filling the form, which can be found at https://telemedicine.med.uni-heidelberg.de/medizinakte/registration_patient.jsf

4. Brachytherapy

Brachytherapy involves placing a source of radiation directly in the tumor or in its close neighborhood. A similar method that is now available, for instance as part of clinical trials in the USA, consists in placing radioactive iodine (124I) via convection-enhanced delivery; during surgery, a special catheter is placed inside the tumor, which is then used to deliver iodine coupled with a monoclonal antibody. The treatment can be administered to patients aged between two and 21.

5. Other methods

Other methods: stereotactic radiosurgery (SRS) and stereotactic fractionated radiotherapy (FRST). Both are considered as preferable with tumor progression or metastasis (they are effective in treating metastatic tumors of the central nervous system, or tumors difficult to access, making traditional surgery impossible or extremely difficult). These methods are very precise, as they involve directing high radiation doses exclusively in the area of the lesion; they require the application of a single dose (SRS) or several large doses (FRST).

Methods that involve spot exposure are considered in recurrent tumors since recurrence occurs most frequently precisely in the areas that had been given large doses of radiation in the course of primary treatment.

SRS and FRST are usually performed with a cyberknife or a gamma knife. Surgery is restricted by size (c. 3 cm) and localization of the tumor. Cyberknife is a modern instrument used in radiosurgery. Its use involves radiation with beams of X radiation of high energy, sent from different directions so that healthy tissue adjacent to the tumor receives the smallest possible dose of ionizing radiation.

Differences between these two methods, which might be relevant for patients, consist in higher precision of the cyberknife (0.05 mm as compared to 0.3 mm for the gamma knife) and the possibility of tracing body movements (which makes it effective in the treatment of organs other than the head). The choice of the best option is always made by doctors, who take into consideration all significant factors.

The drug which is most widely used to increase the effectiveness of radiotherapy is temozolomide.

In the USA (Duke University) doctors researched the effects of supplementing the combination of radiation and temozolomide with bevacizumab in the course of therapy. The main advantage observed was the prolongation of –recurrence-free period and increase of overall survival; the latter was observed also when Avastin was administered only at the detection of the recurrent lesion.

For some time now literature has been appearing on the use of indoximod combined with radiotherapy or without radiotherapy. While temozolomide is part of standard procedures, indoximod is only used in clinical tests. One of the IDO inhibitors (2,3 indoleamine dioxygenase), it is a derivative of tryptophan which inhibits IDO and induces response to treatment in oncological patients. In the preclinical model of glioblastoma, it was demonstrated that supplementing radiotherapy with temozolomide with IDO inhibitors prolongs survival. Indoximode test is available for both children and adult patients (children are already being recruited). In children with newly diagnosed tumors earlier radiotherapy is an excluding factor. More can be found here:
http://investors.linkp.com/static-files/9dfabffe-b4a7-4157-8903-fa46e8026b54.

It seems that the only way to use the drug is through participation in a proper clinical trial (for adults or children), otherwise, it might prove impossible.

Some interesting results followed from a clinical trial carried out several years ago in Japan, where a group of 57 patients with malignant glioblastoma (WHO G III and IV) were tested. Before being given each radiation dose the patients were exposed (for 15 minutes) to hyperbaric oxygen. The results were impressive, especially in the case of patients with stage III tumors. They were also given three chemotherapeutics. Asphyxiation of tumors is considered as the predictive factor in oncological radiotherapy, and for many years doctors have been striving to prevent it, in order to increase the response to oncological treatment. In solid tumors, asphyxiation can occur as the result of rapid growth of tissue, which is not coordinated with the emergence of additional blood vessels. The effect of ionizing radiation should become larger with the increase of the number of free oxygen radicals, which is why tests involving hyperbaric oxygen were undertaken with glioblastoma patients.

Interesting results were also obtained following tests aiming at reduction of radioresistance and chemoresistance: chloroquine, a drug primarily used to cure malaria, was added to the traditional chemotherapeutic, i.e. BCNU. Promising results inspired a study (NCT02378532) which is now recruiting patients in the Netherlands. It is directed at newly diagnosed adult patients who underwent surgery not earlier than six weeks before the beginning of tests. Within the rial, radiotherapy with temozolomide is supplemented with chloroquine.

Yet another drug, tested in terms of its radiosensitizing properties, is OPXIO (earlier XYOTAX), a chemotherapeutic nano preparation. Tests demonstrate that it doubles the progression-free period in patients with polymorphic glioblastoma (the results were presented in 2011, at the ASCO conference). Within this study, patients also underwent radiotherapy combined with temozolomide. It is worth mentioning that In a different study (directed with patients with advanced non-small cell lung cancer) the manufacturer of OPAXIO decided to withdraw their application for its administration, in view of lack of expected advantages. Officially, the medication was only given the status of the so-called orphan drug, granted in 2012 by the FDA as a treatment only in cases of polymorphic glioblastoma.

The effectiveness of radiation is potentially increased by melatonin. In the department of oncological radiotherapy at the Italian hospital in San Gerardo several years ago a research clinical tests were carried involving a group of thirty glioblastoma patients which showed advantages of administering a 20 mg daily dose of melatonin in the course of radiotherapy (longer survival was observed, as well as lower levels of radiation toxicity). The protective effect of melatonin (but also of vitamin E) on brain tissue, combined with radiotherapy, was also reported in 2004 in Neurosurgical Review. Melatonin is an antioxidant, and it should be added that there are some reports claiming the negative effects of antioxidants on the effectiveness of radio- and chemotherapy. This results from the protection of tumor cells from free radicals, which are necessary to destroy cancer cells. It is not our intention to solve this dilemma; we can provide those who might be interested in more details and with internet links to individual papers so that more knowledge should be gained as preparation for meetings with the doctors.