Radiotherapy embraces advanced imaging for high-dose treatments

M Dahele
Radiation oncologist

VU University Medical Center, Amsterdam, 
the Netherlands

BJ Slotman
Professor and chairman
VU University Medical Center, Amsterdam, 
the Netherlands

Advances in radiation oncology can deliver more effective treatments, increase the available therapeutic options and improve patient outcomes. In this article, we look at recent  developments in stereotactic body radiation therapy (SBRT) technology and treatment, and highlight some of the emerging opportunities and challenges in radiation oncology.1

How SBRT differs from conventional RT
Radiation treatment is defined in terms of the total dose (Gray, Gy), the number of individual fractions needed to deliver this, and the time it takes to complete the full treatment. A typical high-dose conventional treatment would be ≥50Gy–70Gy, in once-daily fractions of 1.8Gy–2.0Gy delivered five times per week, over five to seven weeks.

In contrast, SBRT schedules might range from a single fraction of >30Gy to eight fractions of 7.5Gy on alternate days, over two to three weeks. This results in biologically effective doses that may be two to three times higher than with conventional radiotherapy (RT). Conventional RT and SBRT therefore represent two very different treatment approaches. Exploring the reasons for this also explains the significance of several recent technological advances.

Steps need to be taken to minimise the damage to normal tissues, which are frequently located in close proximity to the target tumor. In conventional RT, many small fractions are used to deliver sufficient radiation to provide a chance of tumour eradication. The small fraction size and the interval between individual fractions, combined with prolonged treatment schedules, allow for some normal tissue recovery and reduce the risk of long-term damage.  However, some tumours may regrow during treatment, rendering longer schedules suboptimal.

In contrast, SBRT exploits the fact that large fraction sizes are more damaging to the tumour, delivers fewer total fractions and keeps the overall treatment time much shorter. The challenge with large fractions is that they pose a greater risk of damage to surrounding organs. The SBRT dose therefore needs to be confined as far as possible to the tumour and then fall-off rapidly.

In practice, both conventional and SBRT treatment plans have margins beyond the visible tumour to account for uncertainty in tumour targeting – for example, patient or tumour motion during treatment delivery – and to reduce the chance of missing the target. But the greater the uncertainty margin, the greater the volume of normal tissue that will be irradiated and therefore the greater risk of toxicity.

To reduce these margins from something like 5-10mm to 0-3mm, SBRT makes use of the latest RT planning, irradiation, patient immobilisation and imaging technologies, and takes advantage of the still-potent doses in the fall-off region around the tumour edge. The risk of normal tissue toxicity is further reduced with irradiation techniques that use beams from many angles to spread out the entry dose.

SBRT requires greater accuracy and precision than conventional RT to reduce the chance small margins may result in too high a risk of missing the tumour or of inadvertently delivering too much radiation to a critical organ close to the tumour. The increased complexity with meeting treatment planning and delivery requirements raises possible barriers to SBRT, such as:

• 
Not all centres will have the expertise or desire to deliver SBRT
• The treatment planning may take longer
• 
The larger fraction size and care required to position the patient correctly means that each individual treatment session requires more time.2  

Nonetheless, with improved efficiency, shorter treatment courses and increased training, SBRT is beginning to be more widely offered to selected patients who have localised disease or a limited metastatic burden (for example, ≤5 metastases in total), with the aim of cure or prolonged local tumour control.3 As the technical possibilities with SBRT increase, it can be harder to define RT treatments according to curative or palliative intent, or to restrict high-dose treatments only to patients who meet historic criteria of being candidates for curative-intent RT.

Similar to surgical resection for multiple lung or liver metastases in selected patients, an individualised treatment approach in radiation oncology is entirely consistent with the observation that some patients with few metastases from relatively favourable tumour types (for example breast, prostate, colorectal cancer) may do better than other patients with localised, but less favourable, tumours.

SBRT for early-stage non-small cell lung cancer (NSCLC)
The potential of SBRT is shown by the outcome for patients with early-stage NSCLC located in the periphery of the lung, who may not have been fit enough for, or who may have declined, standard surgical resection. Lung SBRT is a non-invasive, outpatient-based treatment which often requires 30 minutes or less for each fraction.4

Data shows that 90% or more of small tumours can be controlled locally with limited toxicity.5 In non-randomised comparisons, SBRT outperforms conventional RT and it is now being compared to surgery.6,7

Technological advances are helping SBRT
Although SBRT has been used for several years, technological advances enable it to be delivered with greater confidence. Among the most common tumours treated with SBRT are early-stage primary NSCLC and lung, spine or liver metastases, many of which are close to radiosensitive organs such as the oesophagus and spinal cord.  

The following advances are among the most important in confining the highest doses to the tumour, sparing critical organs and reducing uncertainties in the SBRT process (Table 1):

1. 
The radiation treatment plan is designed by systems that rely on computing power and human input. The ability to combine different imaging modalities (computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography [PET]) in these systems allows the target tumour and the normal organs to be more accurately identified.
2. Four-dimensional (4D) imaging for treatment planning, most commonly 4DCT, is the standard of care for moving tumours treated with SBRT (for example, lung tumours). By imaging throughout the breathing cycle it is possible to design a customised treatment plan in which the high-dose RT conforms more precisely to the moving tumour. In many patients, this individualised approach results in smaller treatment volumes than conventional RT with generic margins to account for tumour motion.
3. Once the tumour and normal organs have been identified, computerised planning optimises the distribution of the RT dose and the delivery technique. A medical linear accelerator is used to deliver most external beam RT. Figure 1 illustrates the state-of-the-art Varian TrueBeam™ system recently installed at the VU University Medical Centre (VUmc). In brief, this device, like others of an outwardly similar design, includes a gantry that can be positioned at any desired angle around the patient and from which a beam of high-energy photon RT can be directed at the tumour.
   The beam shape is modified by a multi-leaf collimator (MLC) – two banks of opposing metal leaves that move in and out to create a variable aperture that conforms the beam to the target volume from any projection and can also shield critical organs.
   The position of the MLC leaves can be changed rapidly making it possible to deliver complex treatments to large volumes while the gantry rotates in a continuous arc around the patient – volumetric arc therapy.
   This, combined with the higher radiation dose rates that are now available on many linear accelerators, speeds up SBRT treatment delivery, making it more patient-friendly, and potentially reducing patient movement during delivery.  
4. Changing the MLC aperture also modulates the intensity of the photon flow. This means that the dose delivered by the beam at any given time can be varied in a programmed way, so that the final dose in the tumour adds up to deliver the desired distribution, while at the same time limiting the dose to normal tissues.
   The combination of volumetric arcs and variable photon intensity is called volumetric modulated arc therapy (VMAT), a type of intensity modulated radiation therapy (IMRT). IMRT is one way of conforming high-dose RT regions to the complex tumour shapes that are frequently encountered in SBRT, albeit often at the expense of irradiating greater volumes of tissue to a low dose, the long-term effects of which are not fully understood.
5. To increase the accuracy of treatment delivery, 2D and 3D imaging devices are now routinely mounted on the linear accelerator. 2D images are essentially conventional X-rays, and 3D images are acquired with a modified form of CT – cone-beam CT (CBCT).
   With 2D imaging, the tumour and organs at risk are often not visible, and correct patient and tumour positioning frequently relies on a comparison of the position of bony structures, which is not always optimal. 3D imaging allows for positioning using the target itself, with simultaneous verification of the critical organs.
   By comparing, for example, CBCT images acquired before and during treatment delivery with the planning CT scan – which represents the ideal – the location, shape, volume and motion of the target tumour and normal organs can be evaluated.
   The tumour can then be correctly located by moving the treatment couch that the patient lies on. This process is known as image-guided radiation therapy (IGRT), a key component of SBRT.
6. In order to perform SBRT with the necessary accuracy and consistency, the imaging and treatment components of a linear accelerator must be integrated so that these machines become high-quality imaging and treatment platforms, capable of delivering and verifying treatments with sub-millimetre accuracy. At the same time they must ensure that the patient is stable and comfortable and that the overall process is time-efficient and reliable.

SBRT and new technologies at VUmc
The VUmc has a partnership with Varian Medical Systems of Palo Alto, USA, that is designed to benefit its patient and academic programs. Close collaboration between different specialists means that all of the aforementioned technologies and others are now used to deliver SBRT.

Commencing in 2003, and having now treated about 700 patients, VUmc has one of the largest SBRT programs for lung tumours, and the technique is also in use for other sites including spine/bone, lymph nodes and liver. The centre was an early adopter of 4DCT technology (2003) for treatment planning, and gated RT (2004), where treatment delivery is limited to selected portions of the breathing cycle in order to reduce the radiation dose to organs at risk. Patients with moving tumours routinely undergo 4DCT planning on a General Electric (GE) scanner integrated with the Varian Real-time Position Management™ (RPM) system.

Our standard SBRT treatment technique uses volumetric-modulated arc therapy – RapidArc® – which has been used since 2008 to treat more than 1,000 patients with SBRT or more conventionally fractionated IMRT. IGRT is provided by the Varian On-Board Imager® (OBI) and Novalis ExacTrac® systems (BrainLAB AG, Germany). The SBRT-designated linear accelerators are currently two TrueBeam™, one Novalis Tx™ and one Trilogy™, however each of the six treatment machines is equipped with RapidArc©, OBI and CBCT.

VUmc is the second facility in Europe to begin treatment with the TrueBeam™ system (2010), the intended advantages of which include improved imaging capabilities and integration of imaging and treatment components, the option to deliver radiation at a faster rate, enhanced mechanical stability and greater ease of operation.

Acquiring technology is often easier than making full use of it.8 Indeed, many implementation projects fail or deliver below expectation, with implications for patient treatment and return on investment. Successful implementation should include effective leadership, a belief that the technology is necessary, clear ideas of what to do with it, sufficient technical know-how, teamwork and high expectations.

Niche companies that offer bespoke solutions to some of these challenges are emerging and we have recently added a consulting arm to our department, which currently focuses on providing advice about the implementation of advanced RT technologies.

More than a research tool
Although the current marketing of radiation oncology treatment platforms revolves around terms such as ‘TrueBeam™’, ‘NovalisTx™, ‘CyberKnife®’ and ‘TomoTherapy®’, they all deliver the same type of photon-based radiation and are capable of high-precision treatments with no clear data to show a superiority of one system over another.

It is important to critically consider new technologies in order to determine how they can best be used, and to recall that the foundation of effective treatments are the application of optimised anti-tumour therapy and the minimisation of normal tissue toxicity.9 The ultimate aim of implementing important advances in RT technology is to help achieve these therapeutic goals day in and day out and to try and eradicate or control cancer in more patients.

Disclosures
VU University Medical Centre has research collaborations with Varian Medical Systems, BrainLAB AG and Velocity Medical Solutions

References

1. 
Lo SS et al. Nat Rev Clin Oncol 2010;7:44-54. Erratum in: Nat Rev Clin Oncol 2010;7:422.
2. 
Potters L et al. Int J Radiat Oncol Biol Phys 2010;76:326-32.
3. 
Salama JK et al. Clin Cancer Res 2008;14:5255-9.
4. 
Verbakel WF et al. Radiother Oncol 2009;93:122-4.
5. 
Lagerwaard FJ et al. Int J Radiat Oncol Biol Phys 2008;70:685-92.
6. 
Grutters JP et al. Radiother Oncol 2010;95:32-40.
7. 
Hurkmans CW et al. Radiat Oncol 2009;4:1.
8. 

Mayles WP; Radiotherapy Development Board. Clin Oncol (R Coll Radiol) 2010;22:636-42.
9. 
Glatstein E. Int J Radiat Oncol Biol Phys 2010;76:1283-4.