2.7Particle Radiation Therapy

Particles used for radiation therapy include atomic particles such as electrons, neutrons, and protons (hydrogen), as well as nuclei of atoms such as helium, carbon, and neon. Heavy ion particles such as helium and neon directly damage cellular targets, rather than working through a free radical intermediary that is oxygen dependent, such as with electrons and photons. This may enhance the efficacy of treatment in the hypoxic conditions present in certain tumors such as malignant gliomas. In addition, these heavy ion particles release energy at a certain depth, known as a Bragg peak, which allows the dose to be precisely aimed within the target tissue and provide an increased relative biological effectiveness. They have been used alone and as a boost to conventional photon EBRT (Combs et al. 2010).

Prospective randomized phase III trials comparing protons or carbon ions with precision photon RT have never been conducted. There are limited data on the usage of proton beam RT in GBMs. A study of 15 patients with GBM treated with neon ion irradiation showed median survival of 13–14 months (Castro et al. 1997). In one series of 23 patients, proton RT resulted in a median survival of 20 months following surgery (Fitzek et al. 1999). In the later study a dose equivalent to 90 Gy was prescribed. The authors reported a high rate of tissue necrosis causing progressive neurological symptoms and need for surgical intervention.

Whereas the highly conformal radiation delivery with the use of protons can permit dose escalation, its potential application in treating GBM may be better suited to simply limiting RT-related side effects. Radiation therapy using protons can limit RT-related side effects due to its conformal dose delivery. However, a convincing benefit from dose escalation was not demonstrated so far. These data do not appear to be better than can be achieved with standard photon RT.

Indications for heavy particle include skull base chordomas and chondrosarcomas (Schulz-Ertner and Tsujii 2007). In a retrospective analysis of nonrandomized treatment groups, chordoma patients treated with protons had a significantly higher local control probability in comparison to patients treated with photons (Colli and Al-Mefty 2001).

3Role of Imaging and Treatment Planning

In radiation oncology, imaging is used for clinical staging and treatment planning. Following a course of treatment, imaging is performed at regular intervals to assess for recurrence or, in case of long-term survivors, for second primary malignancies. Radiation oncologists must be familiar with imaging modalities and understand the accuracy and limitations of each. Considering the abovementioned improve-

ments and changes of radiation therapy, the role of imaging becomes more and more important in treatment planning.

An important part of the radiation therapy is the delineation of the gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV). The macroscopic apparent tumor volume is referred to as GTV. The CTV encompasses suspected tumor invasion to the adjusted tissue, lymph vessels, or the draining lymph node stations, which cannot be identified by imaging. Radiation oncologists need expertise in anatomy and knowledge of the different malignancies in order to generate a rational and individual CTV. For example, glioblastoma spread along the white matter does not infiltrate the dura. The planning target volume (PTV) takes into account the accuracy of administration of the radiation therapy. A safety margin is added to the CTV in all directions depending on the accuracy of the treatment facility, the radiotherapy technique, the reproducibility of the daily patient positioning, or the patient movement during treatment.

Standard morphological imaging methods like CT (computed tomography) and MRI (magnetic resonance imaging) enhanced with contrast agents are employed.

In the treatment of GBM, the RT dose is usually delivered to the tumor or resection cavity plus a margin of apparently normal brain tissue. The EORTC guidelines (European Organization for Research and Treatment of Cancer) recommend a margin of 2 cm. The current guidelines of RTOG recommend a 2 cm margin around the resection cavity and the postoperative edema. In a recent study, patterns of failure were similar between the different treatment plans; however the median volume percent of brain irradiated to high doses was significantly smaller for EORTC plans than for RTOG plans (Minniti et al. 2010).

Margins from CTV to PTV became smaller over the years because of improvement of patient positioning using stereotactic cranial masks (STX) or STX whole body mat. Image guidance during RT not only controls the positioning of the patient but also the positioning or filling of inner organs. For this purpose, X-rays, kV imaging or MV imaging, and even cone beam CT are integrated in the linear accelerator.

Advanced imaging modalities for the RT treatment planning require sophisticated software tools to co-register multiple imaging scans. The automatic segmentation of structures can be done according to density information like Hounsfield units or by generating iso-contours by defining thresholds. Some programs can also generate structures like organs at risk from a stored database.

3.1Computed Tomography (CT)

CT plays a primary role in RT treatment planning. Compared with conventional simulation, CT-based planning allows for more accurate target delineation, tighter margins, and less

normal tissue irradiation. CT dose calculation is based on tissue density (Hounsfield units).

3.2Magnetic Resonance Imaging (MRI)

Due to excellent soft tissue contrast and ability to image directly in multiple planes, MRI is the preferred imaging modality for intracranial and spinal tumors. Using modern software, MRI is co-registered to the planning CT.

The contrast enhancement on MRI represents the breakdown of the blood–brain barrier (BBB) (Conventional MR imaging). A disruption of the BBB can also occur from recent operations or radiation therapy (Taal et al. 2008; Clarke and Chang 2009; Wen et al. 2010). Thereby, it is not tumor specific. Additionally, there are sometimes large tumor parts where the BBB is not yet affected and that show no secondary tumor features like enhancement, cerebral edema, and/or compression of other brain structures. These tumor parts as well as non-enhancing lowgrade gliomas are only seen as a hyperintense signal on FLAIR or T2 sequences (Conventional MR imaging). In these cases, the contrast enhancement in T1-weighted MRI sequences underestimates the tumor mass, and consequently, these parts are insufficiently treated.

In addition, as bevacizumab reverses the breakdown of the BBB, it leads to decrease of the contrast enhancement on MRI, pseudo-response, and alteration in tumor behavior. There is evidence that bevacizumab may alter the recurrence pattern of malignant gliomas by suppressing enhancing tumor recurrence more effectively than it suppresses nonenhancing, infiltrative tumor growth (Norden et al. 2008).

Consequently, as mentioned in Conventional MR imaging, certain treatment-related changes after surgery, radiation, and/or chemotherapy, known as pseudo-progression and pseudo-response, cannot be differentiated from tumor tissue (Clarke and Chang 2009; Wen et al. 2010; Brandsma and van den Bent 2009). Because it is self-limiting, it is necessary to separate this phenomenon from radionecrosis, which is a late and progressive radiation injury. It can develop months or even years after the treatment (Giglio and Gilbert 2003).

3.3Positron Emission Tomography (PET)

Imaging methods like positron emission tomography (PET) and single-photon emission computed tomography (SPECT) detect metabolic activity of tumor tissue.

As described in Chap. 7, current diagnostic efforts focus on the use of radiolabeled amino acids (AA) as tracers for brain tumors. Increased AA uptake in gliomas is related to an overexpression of amino acid transporters in the cell membrane. It has been demonstrated that AA uptake in tumor tis-

sue is almost entirely mediated by type L-AA carriers (Langen et al. 2000).

FET and MET were shown to be equally sensitive and specific in clinical practice (Weber et al. 2000; Grosu et al. 2011).

PET and MRI scans of gliomas show considerable differences in tumor volume and position (Fig. 2). In 39 resected GBM patients 11C-MET uptake extended beyond the tumor identified by magnetic resonance imaging in 74 % (Grosu et al. 2005a). In a study of 41 glioma patients, integrating FET uptake into the delineation of GTVs yielded significantly larger volumes in high-grade patients. The congruence of MRI and FET signals was poor with mean uniformity indices of 0.39. MRI-based PTVs missed 17 % of FET PET-/CT-based GTVs (Rieken et al. 2013). Thus, the choice of imaging technique can affect the success of the radiotherapy.

A trial of 44 patients with re-irradiation of recurrent malignant glioma revealed a significantly longer survival time in patients irradiated using MET-PET or IMT SPECT/ CT/MRI image fusion in the treatment planning, in comparison to patients treated based on MRI/CT alone. The median tumor volume was larger in the group with PET/SPECT in comparison to the MRI/CT group, 19 and 14 cm3, respectively (Grosu et al. 2005a, b). The size and location of residual tumor after surgery seen on MET-PET scan differ considerably from abnormalities found on postoperative MRI. In another study of 39 patients, methionine uptake and contrast enhancement on MRI corresponded only in 13 % of the cases (5/39 patients), while in 74 % of the cases, the region of MET uptake was larger than the region of contrast enhancement. Otherwise, the contrast enhancement area extended beyond the MET uptake in 69 % of the 39 patients (Grosu et al. 2005a, b).

Imaging with MRI and FET PEt allowed better distinction between cellular glioma tissue and peritumoral brain tissue than MRI alone. In a study of 31 patients correlating imaging findings with histological specimens, MRI yielded a sensitivity of 96 % for the detection of tumor tissue but a specificity of only 53 %, and combined use of MRI and FET PET yielded a sensitivity of 93 % and a specificity of 94 % (Pauleit et al. 2005).

Lowand high-grade gliomas can be discriminated by using time activity curves from dynamic FET PET (see Chap. 7, Pöpperl et al. 2007). Such diagnostic advantages can be used by radiation oncologist to create IMRT plans with integrated simultaneous boost to the aggressive tumor parts. Preclinical studies even demonstrated that it is possible to detect tumor stem cells by PET using antibody-based tracer (Gaedicke et al. 2014).

PET with radiolabeled AA can be used to visualize the infiltrative growth of gliomas for radiation treatment planning and response monitoring (Götz et al. 2012; Götz and

Fig. 2 Multimodal imaging for target volume delineation in a patient with recurrent glioblastoma. (a) Three-dimensional T1-weighted contrast enhanced MRI. (b) Planning CT. (c) 18F-FET PET/CT with CT-based attenuation correction in gray scale. (d) 18F-FET PET/CT with CT-based attenuation correction in rainbow scale. All images are

co-registered with the planning CT. The red contour corresponds to the contrast enhancement on MRI and the orange contour to the FET uptake on PET. The volume and position of the detected tumor vary depending on the imaging method

Grosu 2013). Patients showing decrease of tracer uptake early after completion of radiochemotherapy had a significant longer progression-free survival and overall survival (Galldiks et al. 2012).

Other tracers like [18F] 3′-deoxy-3′-fluorothymidine (FLT) that visualize cell proliferation are currently under research and might prove to be a valuable tool in response assessment, but are not yet used in clinical practice.

3.4Image-Guided Radiation Therapy (IGRT)

Radiation therapy has essentially always been guided by images. However, today this term defines not only the use of modern imaging modalities incorporating functional or biological information but also the use of imaging to adjust for target motion or positional uncertainty. The RT field of the