It is critical that the regions identified for special attention be defined accurately; areas of active tumor (suitable for high dose) must be identified separately (as gross tumor volume or GTV) from areas suspicious for tumor extension that are suitable for a lower dose (classified as clinical target volume or CTV). The standard approach to defining target volumes in patients with high-grade gliomas is to deliver a certain dose to the contrast enhancing area, as determined from a contrast enhanced T1-weighted magnetic resonance imaging (MRI) or a computed tomography (CT) scan, plus a margin of 1–4 cm. Some protocols deliver an additional dose to the contrast enhancing area itself; a lower dose may be delivered to the T2-weighted region of hyperintensity plus a variable margin.

The gadolinium-enhancing lesion, as seen on T1-weighted MRI, reflects regions where there has been a breakdown of the blood–brain barrier. This may not be a reliable indicator of active tumor due to the presence of nonenhancing tumor tissue or contrast-enhancing necrosis. Therefore, information that can improve the definition of the spatial extent of tumor may improve the ability to define the volumes to which dose should be delivered.The standard approach to defining target volumes in patients with HGG is to add a 1- to 4-cm margin to the contrast enhancing area, as determined from a T1-weighted MRI. The size of this margin has been chosen based upon two traditional lines of reasoning: (1) serial biopsies of patients undergoing craniotomy for malignant gliomas reveal tumor cells more than 3 cm distant from the contrast enhancing margin; (2) about 80% of relapses occur within a 2-cm margin from the original tumor location There are several problems with the standard approach. The gadolinium-enhancing lesion as seen on T1-weighted MRI may not always correspond to the region of active disease due to the presence of nonenhancing tumor tissue and to the presence of contrast enhancing necrosis. Nonspecific processes, such as inflammation or reactive edema formation, also may appear hyperintense on T2-weighted MRI, making it difficult to determine what is and what is not tumor. In addition, serial biopsy studies show tumor cells extending in a variable pattern beyond the enhancement region, in the area of edema, and even in normal appearing brain adjacent to the region of T2 abnormality. Serial biopsy studies have shown also that tumor infiltration tends to follow white matter fiber tracts. A reasonable approach to treatment planning might be to create a plan that simultaneously delivers a conventional dose to the CTV and a higher dose to the GTV. Such an ''integrated boost'' can be delivered using IMRT. If MRSI data were incorporated into the T1 defined GTV volume for grade III patients, this volume (T1 + [AI outside of T1]) would increase by an average of approximately 500%, 300%, or 150%, depending on the AI contour used. The addition of MRSI AI2 data to MRI T2 data in the definition of the CTV (T2 + [AI2 outside of T2]) would increase the volume only by an additional 15%. In contrast, if the MRSI AI2 were used solely to define the CTV, the volume of the CTV would decrease by approximately 20% compared to the use of T2 alone.

For Grade IV patients, there would be similar, but lesser, effects. The addition of MRSI data to the T1 data in the definition of the GTV would increase the average volume (T1 + [AI outside of T1]) by approximately 150%, 60%, or 50% for AI2, AI3, or AI4, respectively. The effect of adding MRSI AI2 data to the T2 data for CTV definition would increase the volume (T2 + [AI2 outside of T2]) by about 10%; if the MRSI AI2 would be used solely to define the CTV, the volume of the CTV would decrease by approximately 40% compared to the use of T2 alone.

It is important to emphasize that these differences varied markedly from patient to patient and that in a given patient, the extension of the AI volume outside the T1c or T2c volumes at each AI level was not uniform. This reinforces the concern over the use of a uniform margin around the T1 or T2 volume when defining treatment volumes. With suspected gross disease, depending on AI level selected, of 39 to 48 and 24 to 27 mm from the T1c border for Grade III and Grade IV tumors, respectively a conventional uniform boost target margin of 5–20 mm would fail to cover all metabolically active disease. This may help explain the high rate of recurrence of malignant gliomas after RT. Finally, it is certainly not clear how the AI should be used, if at all, to delineate dose requirements. IMRT allows different doses to be prescribed to different regions of a target. In order for this to be of value, the dose requirements of those regions must be known. Biopsy correlation studies have shown that an AI of 2 is associated with the presence of tumor cells in 100% of cases. At first pass, it might be felt that regions with an AI greater than 2 are the ones that should be targeted for an integrated boost, either due to higher metabolic activity per cell or to a greater cell density. However, it also could be argued that it is the regions with a lower metabolic activity that will require a higher dose of radiation. For instance, these regions may have depressed metabolic activity due to poor oxygenation, thus requiring a higher dose to control the cell population.