There is no straightforward answer to this question. When a beam of radiation is targeted at the tumor, it immediately exits the brain. Therefore, the patient is not radioactive, and is not “carrying” any radiation, at any point in time. The physical ionization effect of radiation on water within the cells (which is the most common basis for radiation to effect tiisues) occurs almost instantaneously, and this results in events that almost immediately cause damage to a cell’s genetic machinery or DNA. Repair (at least partial) of these DNA lesions generally occurs over a matter of numerous hours. As a consequence of this DNA damage and repair, a cell’s fat can be “sealed” to several possible outcomes including cell death, cell survival without significant proliferation, resistance to treatment and continued proliferation, or accumulation of DNA damaging events, which over time can result in mutations that can cause late effects, even many years out. In normal tissues, damage and repair processes kick in almost immediately, and some of them can cause “early effects” such as hair loss and skin changes over days to weeks, or effects such as swelling which occur over months, or much later effects such as necrosis, scarring, vascular changes, etc. So, the effects of radiation continue over a prolonged period of time.

Patients should always be aware of all the effects of combining various therapies; not only is there positive benefit in many situations, when radiation is combined with drugs, but sometimes, the potential for increased side-effects, or even different side-effects exists. These are highly dependent on a number of variables, including the agent/s used, the way it is combined with radiotherapy, the radiotherapy dose, volume, and fractionation parameters, and therefore, patients should always discuss these issues with both the radiation and medical/neuro-oncologists.

The unraveling of the human genome has led to the cancer genome atlas project, in which detailed genetic analysis of several cancers/tumors is being pursued. Glioblastoma was one of the early candidate tumors for this effort and the recent seminal publications outlining the genetic make-up of this tumor has provided us with several significant insights which can be summarized as follows:

A. Unlike some other tumors, GBM is characterized by multiple genetic modifications, and is rarely, if ever dependent on a “single driver mutation”. This makes the disease challenging to treat, as targeting one single abnormal gene or just one pathway is unlikely to result in a cure.

B. Considerable genetic heterogeneity exists even for this single histopathologic entity, implying multiple possible causative pathways, and variability in terms of response to treatment. This heterogeneity has now been explored in large datasets, allowing prognostic grouping of patients into 3 to 4 distinct classes; theories are emerging as to which pathways and drugs maybe best for the various classes, and clinical trials to test these theories are being pursued.

C. There are some preliminary data allowing us to understand an association between certain therapies and the presence/absence of certain molecular and genetic features which can be either prognostic, or sometimes even predictive markers for certain therapies; example sof this include MGMT methylation status, IDH mutation status, 1p19q deletion status, etc. The exact mechanisms underlying these findings are still being worked out, but the data are resulting in some degree of customization of therapy.

D. In certain lower grade gliomas, especially in children, targeted agents are already being pursued, with good early promising results.

The process for selecting the appropriate radiotherapeutic treatment for a patient takes into account several variables. The first question that needs to be addressed is whether after a comprehensive assessment of the diagnosis, imaging, and the patient’s overall status, including physiologic and metastatic assessement, whether radiation therapy is indicated in either a palliative, curative, ablative, adjuvant, or co-operative (with chemotherapy, etc.) context. If the answer to this first question is yes, the next determination is whether radiotherapy would be used as a sole modality, or in combination with other therapies, and if the latter approach is selected, the exact timing and sequencing become important. This takes into account the potential for synergistic benefit as well as the possibility of additive toxicities. If radiotherapy is to be used either singly or in combination, the next question is appropriate dose and fractionation selection, such as a single fraction, 5 fractions, a 2-week schedule, or a much longer schedule, for example.

The next step in the decision making processing is the actual target selection, and the treatment technical parameters necessary to achieve an appropriate conformal dose to the selected target whilst minimizing the dose to surrounding normal tissue. This would require an assessment of one or more technical approaches to delivering radiotherapy, such as 2D, 3D, IMRT, IGRT, etc. Therefore, the decision-making can be quite complex.

This is an active area for clinical research. There are a number of developments in the breast cancer field that have an impact on this. First, we have now clearly recognized that women with her2+ breast cancer are at higher risk for developing brain metastases and usually this happens later in the course of the disease. We also know that women with breast cancer with brain metastases are a heterogenous group, with quite different survival outcomes, based on a number of variables. For those with a single resectable or symptomatic lesion, surgery remains a good treatment; there is interest in investigating tumor bed radiosurgery after resection for these patients; for those with a limited number of lesions, radiosurgery with or without whole brain radiotherapy is a good approach, although there is an increasing trend toward radiosurgery alone followed by salvage as necessary, and this aspect remains under active investigation. A number of clinical trials are in development, attempting to combine focal radiosurgery plus potentially active drugs that might cross the blood-brain barrier and reduce the emergence of new metastases. This area remains investigational. In patients with multiple lesions, approaches for combining whole brain radiotherapy with agents that might enhance the efficacy of radiotherapy are being studied; examples include agents such as veliparib, lapatinib, and others. Cognitive effects after whole brain radiotherapy remain an important consideration and both physical methods and drug approaches to modify these are being evaluated, and include techniquessuch as hippocampal avoidance whole brain radiotherapy, and the investigational use of agents such as memantine and ACE inhibitors. Agents that could possibly have a direct effect on brain metastases are also in clinical trials, mostly for patientswhose disease has progressed after prior therapies.

Stereotactic radiosurgery has a well-established place in the management of certain conditions, for example patients with single brain metastases where survival can be prolonged, for patients with arteriovenousmalformations which can be obliterated, for trigeminal neuralgia, which can be controlled, for cluster headaches, etc. Increasingly, radiosurgery is being used in several patients with benign tumors such as schwannomas (especially vestibular, but also others), meningiomas, secreting pituitary adenomas, etc. Its role in low gradegliomas is ill-defined. In patients with high grade gliomas, no categorical survival difference has been identified with the use of radiosurgery, but this area remains under investigation; in contrast, for recurrent GBM, at least in well-selected patients, there maybe a role for this treatment.

However, the biggest growth area for radiosurgery is brain metastases. For patients with up to 4 brain metastases, the addition of radiosurgery to whole brain radiotherapy clearly improves local control. Increasingly, many patients with several brain metastases are being treated with radiosurgery alone, without whole brain radiotherapy, but it is important to remember that this also remains the subject of controversy and clinical trials.

Swelling identified only on imaging, and if asymptomatic, and not causing significant mass effect on the MRI, can often be followed without actual intervention.

In contrast, extreme swelling resulting in hydrocephalus, or herniation or impending major neurologic deficit may require immediate surgical intervention. Most cases fall somewhere in between, and it is common practice to start with a somewhat high dose of steroids such as 4 mg 4 times a day of dexamethasone followed by a taper to get down to the minimum steroid dose necessary, as reasonably quickly as tolerated by the patient. When using steroids, the patient must be cautioned about the plethora of side effects associated with these agents, and careful follow-up requires evaluation focused on these side effects as well. Steroids should be discontinued as rapidly as possible. Sometimes, it maybe necessary to re-initiate steroids. If the swelling is actually caused by radiation necrosis which does not require surgery, bevacizumab is increasingly being used, and is quite effective. A number of other options such as hyperosmotic mannitol, hyperbaric oxygen, and others are available, with limited value.

The phrase NED is a bit of a reach and a stretch for many brain tumors because NED implies “no evidence for disease”, whereas in reality, after radiotherapy, there is almost always a visible tumor that needs to be monitored to ensure that it is not growing.

The follow-up guidelines vary based on the actual diagnosis and the time that has elapsed since completing radiotherapy. In general, for almost all patients, it is common practice to evaluate patients approximately 1 month after completing radiotherapy to ensure that any acute or immediate side effects have resolved. Thereafter, the frequency of follow-up varies based on several parameters. For example, for benign tumors such as meningioma, vestibular schwannoma, etc., it is not uncommon to see the patient at 6 monthly intervals for the first year, with MR imaging and then annually thereafter. For patients with low gradeglioma, the initial follow-up is a little more frequent, such as every 4 months or so but is then progressively lengthened.

For malignant tumors, the opposite is true, in that the follow-up is more rigorous and more frequent. For example, for patients with brain metastases treated with radiosurgery alone, the initial imaging and follow-up is frequent, such as for example at months 1, 3, 6, etc, and the reason for this is to identify any new lesions that may develop as a consequence of withholding whole brain radiotherapy. For patients with malignant glioma, such as glioblastoma, the follow-up and imaging is often co-ordinated with the chemotherapy doctor (medical or neuro-oncologist), and typically occurs every 2 to 3 months to follow things like tumor response, pseudoprogression, tumor progression, etc. These follow-up visits are also important for the purposes of tapering steroids, adjusting the doses of seizure medications, etc. In patients treated with mostly a palliative intent, the follow-up visits are minimized to reduce the burden on the patient, and visits and imaging is often performed on an “as needed” basis.

A corollary question is when do you stop following? There are no good guidelines for this part of the question, since this is not a question that has been studied prospectively; for patients with benign tumors, some physicians stop imaging (and sometimes follow-up) after 5 years, but relapses/recurrences have been described 15 years and beyond, and so there is no categorical answer for this. For patients who decline because their disease is progressing, and if no further therapeutic options are available, frequent visits and scans may only increase the burden on the patients, and this should be wisely considered.