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R e v i e w o n c o l o g y Image-guided radiotherapy A u tho rs M. De Ridder, D. Verellen, N. Linthout, K. Tournel, S. Bral, G. Storme Key wo rds Radiotherapy, image-guided radiotherapy, intensity-modulated radiotherapy, partial tumor boost, respiratory gating Summary Progress in radiotherapy is guided by the need to realize improved dose distributions, i.e. the ability to reduce the treatment volume towards the target volume and still ensuring coverage of that target volume in all dimensions. These advancements are usually not to be attributed to a single event, but rather a combination of many small improvements that together enable a superior result. Image-guidance is an important link in the treatment chain and is as such a major factor in this synergistic process. Imageguided radiation therapy (IGRT) aims at instant knowledge of the tumor volume location during irradiation or alternatively, studying the motion and volume changes of the target volume, allowing management of these effects in the Introduction The control rate after radiotherapy is proportional to the dose of radiation that is delivered to the tumor, which is traditionally explained in a linear, quadratic model of cell killing. The limiting factor in escalating the radiation dose towards tumoricidal levels is the collateral damage caused to nearby healthy tissues. In addition to tolerance dose, the irradiated volume of surrounding healthy tissues is a critical parameter in the development of radiation induced toxicity. Traditionally, the irradiated volume encompasses the gross tumor volume (GTV) and the area at risk for microscopic spread. To assure a proper coverage of this clinical target volume (CTV), a margin is added to compensate for daily positioning errors and internal motion of organs, resulting in the planning target volume (PTV), to which the radiation dose is prescribed.1,2 One way to escalate the dose to the tumor without increasing the irradiated volume of surrounding B E L G I A N J O U R N A L O F M E D I C A L treatment planning process. The limited ability to control the tumor’s location, compromises the accuracy with which radiation can be delivered to tumor-bearing tissue. The resultant larger treatment volumes required to accommodate target uncertainty may limit the radiation dose, owing to the larger amounts of surrounding normal tissue exposure. With IGRT these volumes can be optimized and tumoricidal doses may be delivered, achieving maximum tumour control with minimal complications. Moreover, with the ability of high precision dose delivery and real-time knowledge of the target volume location, IGRT has initiated the exploration of new indications in radiotherapy, previously considered to be unfeasible. 5255-63) tissue, is to create a conformal dose distribution that tightly matches the shape of the target volume. This became possible due to the evolution in computerized planning systems and sophisticated dose delivery systems, such as intensity modulated radiotherapy (IMRT) and conformal arc therapy (Figure 1 on page 256).3 To further decrease the irradiated volume of nearby organs, it is necessary to decrease the PTV itself and thereby limit the volume of healthy tissues that is intentionally irradiated. This can be achieved with the implementation of image guided radiotherapy (IGRT), which enables instant knowledge of the tumor location and even control of organ motion during treatment.4 As a result, the margins can be decreased from centimetres to millimetres.5 For a spherical tumor of 5 cm for instance, a reduction of 2.0 cm to 0.5 cm safety margin results in decreasing the irradiated volume of surrounding organs from 316 cm3 to 48 cm3. O N C O L O G Y vol. 2 issue 5 - 2008 255 R e v i e w o n c o l o g y Figure 1. Intensity-modulated radiotherapy (helical tomotherapy) for rectal cancer. Dose distribution of a plan without (left) and with (right) a simultaneous integrated radiation boost. The difference dose levels (Gray) are represented by corresponding colours. Note the dose painting around the planning target volume to spare the small bowel (delineated in black) and the bladder (delineated in blue) and the steep dose-fall from 55.2 to 46 Gy. Clinical considerations for IGRT The therapeutic success of a radiation treatment is determined by the balance between tumor control and normal tissue complication probability (TCP-NTCP balance). Indeed, in a high proportion of patients the biological dose necessary for tumor eradication can not be delivered because of a high probability of complications due to collateral damage to surrounding tissues. The principal goal of radiation research is to improve the TCPNTCP balance. This can be achieved by combining radiotherapy with chemotherapy, considering the synergistic anti-tumoral effects of both modalities. Randomized trials in a variety of solid tumors have demonstrated that combined modality treatment improves local control and overall survival. However, this also significantly increases toxicity, which can be explained by a lack of specificity of both radiation and chemotherapy for cancer cells as opposed to rapidly dividing normal cells.6,7 Ongoing trials are evaluating whether the use of CRT-IGRT may decrease the NTCP of combined chemoradiotherapy. Modern radiosensitizing strategies try to exploit the biological specificity of tumors by targeting growth-factors and pro-angiogenic pathways such as EGF and VEGF, or by targeting specific features of the tumor microenvironment, such as hypoxia or the pro-inflammatory tumor infiltrate.8,9 Recent evolutions in CRT-IGRT offer an alternative strategy to improve the TCP-NTCP balance. New delivery techniques such as IMRT enable complex dose distributions with sharp dose gradients, allowing an increase of the radiation dose to the target volumes, without increasing the irradiation of nearby tissues.10 However, it is widely recognized 256 vol. 2 issue 5 - 2008 that there are unavoidable uncertainties in the process of planning and delivering radiotherapy. Some of these relate to the identification of the extent of microscopic disease spread, while others are associated with the delivery of radiation itself. It is important that the magnitudes of these uncertainties are well understood and minimized whenever feasible and that the possible influence on the outcome of treatment is estimated correctly. In “conventional” radiotherapy, information about the extent and frequency of these uncertainties is crucial in determining the extent of safety margin around the tumor that is necessary to ensure “adequate” tumor coverage and in assessing whether the goal of sparing a critical organ is likely to be achieved. With the introduction of IMRT, exact knowledge and adjustment of appropriate margins become of primary importance, since the resulting sharp dose gradients are unforgiving with respect to misalignment and motion. This misalignment or motion may result in unacceptable high irradiation doses to healthy tissue or important under-dosage of the target volume. Nowadays, IGRT serves multiple purposes: (1) optimal reduction of treatment margins, (2) the concept of “dose-painting-by-numbers” and hypofractionated radiotherapy require almost exact knowledge of the anatomy during dose delivery in real-time, and (3) interactive adaptation of the treatment based on daily assessment of changes in tumor volume and response. CRT-IGRT was initially implemented in dose escalation protocols in prostate cancer, which resulted in improved biochemical control rates, while preventing an increase in rectal and bladder complications. A retrospective analysis of 2,991 patients that were consecutively treated, was reported by Kupelian and colleagues and showed equal biochemical failure rates for prostatectomy, permanent seed implantation and high dose radiotherapy (> 72 Gy), while the outcome was significantly worse for standard dose radiotherapy (< 72 Gy).11 This study nicely illustrated that due to the ability of CRT-IGRT in delivering higher doses, radiotherapy may become an alternative for surgery. However, prospective randomized trials comparing radiotherapy directly to surgery are difficult to realize, considering that most physicians and patients have a preference for either treatment modality, based on local expertise and the (un)availability of CRT-IGRT. Alternatively, CRT-IGRT can be used to spare normal tissues, while maintaining the dose to the target volume. This approach was successfully implemented in the B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y Figure 2. Dose painting by numbers. Do It Yourself Flowers, by Andy Warhol (1962). The concept of painting by numbers translates to radiotherapy in that the colour coding obtained from, for instance, PET information (metabolic information) can be quantified and translated into biological effective dose to be delivered with IMRT. treatment of head-and-neck cancer, where sparing of parotid glands has decreased the incidence of xerostomia (or dry mouth) improving the quality of life. This approach was also used in the preoperative treatment of rectal cancer, where helical tomotherapy allowed a decrease in acute gastrointestinal and urinary toxicity.12,13 Because intra-abdominal organs, such as the small bowel, the stomach, the liver and the kidneys, are more radiosensitive than most solid tumors, radiotherapy is not commonly used for intra-abdominal malignancies. CRT-IGRT offers the possibility to prescribe tumoricidal radiation doses, while limiting the irradiated volume of these organs and opens a new therapeutic avenue for a variety of GI cancers, such as hepatic malignancies and pancreatic cancer. In conventional radiotherapy, a homogenous or uniform dose is generally delivered to the target volume, without violating the tolerance of the nearby tissues. From a biological point of view it looks more attractive to prescribe non-uniform target dose distributions. Models suggest that a significant increase in TCP may be gained from partial tumor boost doses delivered to 60% or more of the tumor volume.14,15 Theoretically, this approach can decrease the local recurrence rate by enabling a large volume of the tumor to receive a lethal dose, and preventing re-population of tumor cells located in the boost volume. The concept of partial tumor boosts was developed many years ago, but is regaining interest since the combination of IMRT B E L G I A N J O U R N A L O F M E D I C A L and IGRT allows its clinical implementation. In addition, recent progress in biological and physical imaging modalities such as positron emission tomography (PET), single photon emission computed tomography (SPECT), dynamic contrast enhanced magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) can provide spatial information on the biological and physical characteristics of the tumor, which may identify different levels of radioresistance.16 This can be integrated into the treatment planning procedure, allowing biologically relevant dose optimization taking into account estimations of hypoxia, cell proliferation rate and cell density.17 The technique of applying nonuniform dose prescriptions is called voxel-intensity based IMRT or “dose-painting-by-numbers”. The intensity of the radiation varies from voxel to voxel according to the estimated level of radioresistance, as assessed by biological imaging (Figure 2). This strategy is currently being explored in experimental models and early clinical trials.18 Finally, the ability of high precision dose delivery is initiating a revision of generally accepted fractionation schemes and concepts of radiobiology. Conventional radiation schedules with curative intention consist of 25-35 daily fractions of 1.8-2.0 Gy. Dividing the radiation dose into such a large number of relatively small fractions decreases NTCP, because of sublethal damage repair between dose fractions and cellular repopulation. At the same time, fractionation increases TCP because of reoxygenation of O N C O L O G Y vol. 2 issue 5 - 2008 257 R e v i e w o n c o l o g y tumors and reassortment of cancer cells into radiosensitive phases of the cell cycle. However, these conventional fractionation schedules are often a burden for patients, requiring daily visits to the hospital for 5-7 weeks and require considerable machine time, which is an important factor in the economics of radiation therapy. These considerations led to the development of hypofractionated radiotherapy, which by definition uses fraction doses of more than 2 Gy. Hypofractionation was introduced in clinics in the early sixties for the treatment of breast cancer, where 3- and a 5-day-treatment-a-week were compared.19 This and other studies showed that fraction sizes of more than 2 Gy produce significantly more unfavourable sequelae compared to conventional fractionation. Hence higher fraction doses were abandoned for the next 30-40 years to biologically limit NTCP.20 As the introduction of CRT-IGRT offers a physical way to spare nearby tissues the concept of hypofractionation is currently being revisited. If larger radiation fractions are given daily, it results in an acceleration of the treatment (shorter overall treatment time) reducing repopulation of rapidly proliferating tumors and increasing TCP.21 The recent (r)evolution in IGRT has driven the development of stereotactic body radiation therapy (SBRT), an extreme form of hypofractionation that delivers an ablative dose of radiation in few fractions, capable of disrupting tumor mitosis and other cellular functions. Several phase I/II studies reported high levels of local control in lung cancer and liver metastasis, with acceptable toxicity.22-24 Randomized trials that compare SBRT to surgery have been initiated. Image-guidance techniques As this is a review on IGRT, immobilization techniques and margin recipes will not be covered. Yet, it is important to realize that in order to obtain its full potential, IGRT will need to be combined optimally with immobilization devices to help the patient maintain a certain position and margins counteracing inter-observer variability in volume delineation, compensating for uncertainties in the involvement of disease and representing the remaining geometric uncertainty. The clinical application of IGRT for patient set-up verification/correction can generally be classified in the off-line or on-line approach. The former monitors the position of the patient during a limited number of fractions and adapts the safety margins and/or treatment plan accordingly. The online approach offers the possibility of reducing most 258 vol. 2 issue 5 - 2008 geometric errors (both systematic and random), yet requires automation of quantification and correction of target localization errors to make it efficient in clinical routine. An extremely important feature of IGRT is the ability to register the images-of-theday to a reference image-set, that usually has been generated at the time of treatment planning, representing the ideal situation (i.e. perfect alignment of treatment beam and target volume). The purpose of image registration is to find the transformation (translation, rotation and preferably deformation) that maps one set into the other to obtain the corresponding adjustments required to align target volume and treatment beam as accurate as possible. Peripheral solutions for IGRT The concept “peripheral” refers to in-room imaging devices that are not mounted on the treatment device. Being independent of the beam delivery device, peripheral solutions for IGRT offer the advantage that they can be used to cope with organ motion and/or patient motion during irradiation (so called intra-fraction motion). A disadvantage of this concept is that the system needs to be carefully calibrated with respect to the machine’s isocentre setting, which results in an additional source of uncertainty. The combination of multiple X-ray source / detector systems has been introduced to solve the inherent 2D limitation in target localization of using megavolt (MV) images generated with the high energy treatment beam such as portal films or Electronic Portal Imaging Devices (EPIDs). The approach of using diagnostic X-rays for treatment set-up verification offers a threefold advantage: (1) Image quality (a well-documented problem in MV-based imaging) is no longer an issue, (2) patient dose becomes less important compared to daily MV imaging and (3) the modality can be used in fluoroscopic mode during treatment. The Mitsubishi Electronics Co. in collaboration with the Hokkaido University developed a room mounted kV-imaging device, soon followed by similar reports from the University Hospital Brussels in collaboration with BrainLAB AG on the ExacTrac/NovalisBody system using a combination of infrared reflective markers and a robotic couch to accurately correct for both translational and rotational set-up errors (Figure 3).25,26,27 Alternatively the Cyberknife approach (Accuray Inc.) leaves the patient undisturbed applying a linear accelerator on a robotic arm featuring 6 degrees-of-freedom to adapt the beam delivery device according the image information. Room mounted X-ray imaging systems B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y Figure 3. The image guidance of the Novalis® System is used for target localization and consists of 2 X-ray tubes placed in holes in the floor (central bottom of upper image) and two Amorphous Silicon detectors mounted at the treatment room ceiling (central top of upper image). The configuration is as such that the beam axes of both tubes cross the treatment beams axis isocentrically. The lower images show the 2 digitally reconstructed radiographs (left images) and the 2 X-ray images (right images) that are registered with each other in order to define the possible correction of the patient’s setup with respect to the treatment machine to correspond with the treatment planning. This registration can be based on bony structures or implanted gold markers. The latter is visible in these images. are particularly suitable for real-time internal fiducial marker (e.g. implanted radio-opaque objects) tracking during treatment. The X-ray sources and imagers are fixed on the floor or ceiling to provide high mechanical precision, assuming a proper calibration has been established. A major disadvantage of this solution is the inability to visualize soft tissue requiring surrogate structures (bony landmarks or implanted radio-opaque markers) to acquire positional information of the target volume. Another drawback is the lack of information concerning the spatial relationship between target and adjacent organs at risk during the course of treatment. Diagnostic CT scanners have been introduced in the treatment room because soft tissue can be visualised offering the advantage that no surrogate is required to visualize the target. The scanner may be positioned over the treatment couch using rails, and/or the treatment couch may be used to transport the patient into the bore of the CT gantry. On-board solutions On-board solutions refer to imaging devices that are physically attached to the treatment delivery system. B E L G I A N J O U R N A L O F M E D I C A L Major advantage of this approach is the utilisation of the actual treatment beam to ensure alignment of beam and target (i.e. replacing the conventional radiographic films or portals). In addition to this the EPID can be used for dose measurements, which is extremely useful in detecting differences between actual patient data as encountered during treatment and those applied during treatment planning.28 Being a planar (as opposed to volumetric) imaging device mounted to the treatment delivery system distal to the patient, it requires multiple gantry positions to obtain 3D information. The latter has been solved by introducing an additional X-ray source / detector system perpendicular to the treatment beam axis, or 2 additional gantry mounted X-ray systems with central axes intersecting with each other at the linac’s isocentre. Moreover, both the EPID imager as well as an orthogonally mounted X-ray imaging device, can be used to acquire cone beam volumetric CT data (CB-CT).29 These CB-based solutions offer sufficient soft tissue visualization, avoiding the need for surrogates in localizing most target volumes or critical structures. On the other hand, volumetric imaging during beam-on is not possible and limited O N C O L O G Y vol. 2 issue 5 - 2008 259 R e v i e w o n c o l o g y Figure 4. Combined computed tomography and daily MVCT image data. Example of an overlay (axial and sagittal crosssections are shown) of planning computes tomography data (grey) and daily Megavolt computed tomography data (yellow), prior to (upper images) and after adjustment (lower images). to positioning the patient prior to treatment. The major weakness of the gantry-mounted systems is the sub-optimal mechanical precision (e.g. gantry sagging) and the scatter radiation from the patient to the imagers. Integrated solutions “Integrated solution” refers to a concept that grew out of previous developments, but was designed from the start for a certain purpose. The helical tomotherapy (TomoTherapy Inc.) approach is such an example, where the concept of an add-on sequential tomotherapy device has been combined with helical CT-scanning obtaining a 2-in-1 concept. It is a treatment modality in which IMRT is delivered in a rotational fashion using a 6 MV linac mounted to a ring-based gantry. Simultaneously, the patient is slowly translated through the bore allowing high modulation and conformity of the dose distribution. From the patient’s point of view the source describes a helical trajectory.30 The continuously rotating gantry combined with a CT-detector array system allows MVCT imaging and can be used for in vivo dose transmission measurements for dose verification. Basically it is a CT-scanner where the diagnostic X-ray tube has been replaced with a 6 MV linac and the collimating jaws (or shutters) are replaced 260 vol. 2 issue 5 - 2008 with a binary collimator consisting of small high density metal leaves, creating 64 small beams that can be switched on/off rapidly for IMRT by varying the fraction of opening time during rotation. In a way similar to diagnostic CT, the patient is treated in slices by a narrow photon beam. CT-image acquisition is accomplished with all leaves open prior to treatment (Figure 4). A logical “next-step” is to introduce MRI in IGRT as it offers superior soft tissue contrast compared to radiographic imaging. At the university of Utrecht a prototype is being designed, combining a linac mounted on a ring-based gantry and a 1.5T MRI device. Inherent to its design, the approach is limited by interaction of the radio-frequency (RF) signal used for MR imaging with the RF-pulses required for electron acceleration in the linac and the influence of the strong magnetic field from MRI on the dose absorption process. To cope with these limitations, Dempsey et al (James Dempsey, personal communication, 2006) designed a 0.3T MRI combined with 3 60Co-sources equipped with multileaf collimators (MLC) for IMRT mounted on a ring-based gantry. Both MRI concepts are promising, but are still in the development phase. Image-guidance and motion management Respiratory motion affects all tumor sites in the thorax and some in the abdominal region, and again, motion control will allow reduction of irradiated healthy tissues and possible escalation of dose to the target volume.31 Apart from techniques to accurately describe motion, different methods are being developed for motion management during treatment, such as forced shallow breathing by abdominal compression or breath-holding, motion-encompassing techniques and breathing synchronized techniques (e.g. respiratory gating and real-time tracking). Using a stereotactic body frame to suppress breathing induced motion, Wulf et al showed that with a margin for target variability of 5 mm (antero-posterior and latero-lateral) and 10 mm (cranio-caudal) about 12-16% of the targets might be missed partially.32 Therefore, they concluded that CT-verification prior to each treatment session is recommended to detect these targets with increased reproducibility. Motion encompassing techniques refer to the idea of incorporating information on tumor motion into the treatment planning process, either by introducing patient individualized margins or using this information in the optimization procedure. Internal motion can be assessed by time resolved imaging techniques such as “slow” CT scanning or PET, which offers infor- B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y mation on tumor position probability due to its slow acquisition time. Alternatively, multiple fast CT acquisitions during the respiratory cycle can be used describing the target’s motion during the respiratory cycle. However, respiratory motion is irregular and no general respiratory patterns exist that can be assumed by observation prior to treatment. Mostly, respiratory-synchronized techniques offer the optimal solution. It should be noted that sometimes the object being measured for motion is the tumor itself, an artificial marker implanted in or near the tumor or a surrogate organ such as the diaphragm. Moreover, the breathing pattern itself is usually obtained from an external signal allowing real-time observation (e.g. infrared reflective markers placed on the patient’s surface, spirometers or a flexible bellow) and the mechanical coupling with the tumor is often weak, resulting in complex relationships. Respiratory-synchronized techniques need to establish a correlation between the real-time external breathing signal and the internal tumor motion and this correlation needs to be verified with regular intervals during the course of treatment. Based on 4D CT measurements, Lu et al have shown that the internal motion is strongly related to the amplitude of the external signal (the signal for respiratory motion can be characterized by amplitude or phase).26 Respiratory gating involves the administration of radiation during certain intervals within a particular portion of the patient’s breathing cycle, commonly referred to as the “gate”. The choice of the gate width is a tradeoff between minimizing motion within the gate and beam-on time. Breath-holding techniques are being introduced to optimise the duty cycle. Some studies have shown the anatomic position of the tumor to be more reproducible at end respiration. On the other hand, when breath-holding techniques are introduced at (moderate) deep inspiration, the relative damage to healthy lung tissue can be reduced and it seems to be more comfortable for the patient. Another way of accommodating respiratory motion is repositioning the radiation beam dynamically to follow the tumor’s changing position, referred to as real-time tumor tracking. Conclusion This review paper demonstrates that the recent progress in radiotherapy, resulting from the synergistic combination of improved dose distributions (conformal radiotherapy or CRT) and frequent imaging (IGRT) during the course of radiotherapy, B E L G I A N J O U R N A L O F M E D I C A L has drastically improved the quality of radiotherapy and has broadened its possibilities and indications. High precision radiotherapy is indicated in those situations where the dose that has to be delivered to a tumor exceeds the tolerance dose of the surrounding tissues. Since the progress in CRT and IGRT were simultaneously implemented in clinical use, it is difficult to discriminate the relative contribution of each modality. Glossary • Image-guided radiotherapy (IGRT): Frequent imaging in the treatment room during a course of radiation therapy to guide the treatment process. • Conformal radiotherapy (CRT): Describes the aim in radiotherapy of conforming or shaping the high-dose volume to the planning target volume. Alternatively, conformal avoidance refers to sparing of organs at risk. To do so, dose delivery systems such as conformal arc therapy and intensity modulated radiotherapy (IMRT) are being used. • Intensity-modulated radiotherapy (IMRT): Radiotherapy technique with varying intensity of irradiation within a radiation field. This can be obtained by using differential dose absorbers or by varying the time of radiation at different points. • Tomotherapy: Therapy analogue of computed tomography. A specially designed collimator generates an intensity modulated profile and at the same time the gantry rotates around the long axis of the patient and as such irradiates a slice of the patient. One approach is the slice-by-slice arc rotation approach, where the patient is translated longitudinally between consecutively gantry rotations to treat sequential transaxial slices. In helical tomotherapy, the patient is being translated longitudinally, slowly and continuously, during the gantry rotation. References 1. International Commission on Radiation Units and Measurements: Prescribing, Recording and Reporting Photon Beam Therapy. IUCR Report 50. Bethesda, Maryland; 1993. 2. International Commission on Radiation Units and Measurements: Prescribing, Recording and Reporting Photon Beam Therapy. ICRU Report 62. Bethesda, Maryland; 1999. 3. Bernier J, Hall EJ, Giaccia A. Radiation oncology: a century of achievements. Nat Rev Cancer 2004;4:737-747. 4. Verellen D, De Ridder M, Linthout N, et al. Innovations in image-guided radiotherapy. Nat Rev Cancer 2007;7:949-960. O N C O L O G Y vol. 2 issue 5 - 2008 261 R e v i e w o n c o l o g y Key messages for clinical practice 1. In order to assure proper coverage of the clinical target volume (CTV) by radiation, a margin needs to be added, compensating for daily positioning errors and internal motion of organs, resulting in the planning target volume (PTV). Therefore the PTV includes normal tissues nearby the tumor, to which radiation is intentionally delivered. 2.The dose of radiotherapy necessary to control a tumor may often not be delivered because of the high probability of complications in nearby normal tissues. This problem can be tackled by the generation of conformal dose distributions that tightly match the volume of the PTV and/or by decreasing the amount of normal tissue in the PTV. 3.IGRT is defined as frequent imaging in the treatment room allowing treatment decisions made on the basis of these images. IGRT aims at decreasing CTV-to-PTV margins from centimetres to millimetres. 4.The synergy between conformal radiotherapy (CRT) and IGRT has drastically improved the quality of radiotherapy and has broadened its possibilities and indications. The clinical implementations of CRT-IGRT enabled dose escalation, conformal sparing, non-uniform dose distributions and initiated a revision of fractionation schedules. 5. Tournel K, De Ridder M, Engels B, et al. Assessment of inter- and intra-fraction movement in the treatment of rectal cancer patients on Tomotherapy using daily MV-CT. Int J Radiat Oncol Biol Phys 2008; in press. 6. Schaake-Koning C, Van Den BW, Dalesio O, et al. Effects of concomitant cisplatin and radiotherapy on inoperable nonsmall-cell lung cancer. N Engl J Med 1992;20;326:524-530. 7. Herskovic A, Martz K, Al Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 1992;326:1593-1598. 8. Nyati MK, Morgan MA, Feng FY, et al. Integration of EGFR inhibitors with radiochemotherapy. Nat Rev Cancer 2006;6:876-885. 9. De Ridder M, Verovski VN, Darville MI, et al. Macrophages enhance the radiosensitizing activity of lipid A: a novel role for immune cells in tumor cell radioresponse. Int J Radiat Oncol Biol Phys 2004;60:598-606. 10. Intensity-modulated radiation therapy collaborative working group. Intensity-modulated radiotherapy: current status and issues of interest. Int J Radiat Oncol Biol Phys 2001;51:880-914. 11. Kupelian PA, Potters L, Khuntia D, et al. Radical prostatectomy, external beam radiotherapy <72 Gy, external beam radiotherapy > or =72 Gy, permanent seed implantation, or combined seeds/external beam radiotherapy for stage T1-T2 prostate cancer. Int J Radiat Oncol Biol Phys 2004;58:25-33. 262 vol. 2 issue 5 - 2008 12. De Ridder M, Tournel K, Van Nieuwenhove Y, et al. Phase II study of preoperative helical tomotherapy for rectal cancer. Int J Radiat Oncol Biol Phys 2008;70:728-734. 13. Pow EH, Kwong DL, McMillan AS, et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: Initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys 2006;66:981-991. 14. Tome WA, Fowler JF. Selective boosting of tumor subvolumes. Int J Radiat Oncol Biol Phys 2000;48:593-599. 15. Deasy JO. Partial tumor boosts: even more attractive than theory predicts? Int J Radiat Oncol Biol Phys 2001;51:279-280. 16. Gambhir SS. Molecular imaging of cancer with positron emission tomography. Nat Rev Cancer 2002;2:683-693. 17. Payne GS, Leach MO. Applications of magnetic resonance spectroscopy in radiotherapy treatment planning. Br J Radiol 200;79:S16-S26. 18. Ling CC, Humm J, Larson S, et al. Towards multidimensional radiotherapy (MD-CRT): biological imaging and biological conformality. Int J Radiat Oncol Biol Phys 2000;47:551-560. 19. Fletcher GH. Hypofractionation: lessons from complications. Radiother Oncol 1991;20:10-15. 20. Harrison D, Crennan E, Cruickshank D, et al. Hypofractionation reduces the therapeutic ratio in early glottic carcinoma. Int J Radiat Oncol Biol Phys 1988;15:365-372. 21. Kim JJ, Tannock IF. Repopulation of cancer cells during therapy: an important cause of treatment failure. Nat Rev B E L G I A N J O U R N A L O F M E D I C A L O N C O L O G Y Cancer 2005;5:516-525. 22. Herfarth KK, Debus J, Lohr F, et al. Stereotactic singledose radiation therapy of liver tumors: results of a phase I/II trial. J Clin Oncol 2001;19:164-170. 23. Bral S, Van Parijs H, Soete G, et al. A feasibility study of image-guided hypofractionated conformal arc therapy for inoperable patients with localized non-small cell lung cancer. Radiother Oncol 2007;84:252-256. 24. Nagata Y, Takayama K, Matsuo Y, et al. Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame. Int J Radiat Oncol Biol Phys 2005;63:1427-1431. 25. Shirato H, Shimizu S, Kitamura K, et al. Four-dimensional treatment planning and fluoroscopic real-time tumor tracking radiotherapy for moving tumor. Int J Radiat Oncol Biol Phys 2000;48:435-442. 26. Verellen D, Soete G, Linthout N, et al. Quality assurance of a system for improved target localization and patient set-up that combines real-time infrared tracking and stereoscopic X-ray imaging. Radiother Oncol 2003;67:129-141. 27. Linthout N, Verellen D, Tournel K, et al. Assessment of secondary patient motion induced by automated couch movement during on-line 6 dimensional repositioning in prostate cancer treatment. Radiother Oncol 2007;83:168-174. 28. Herman MG, Balter JM, Jaffray DA, et al. Clinical use of electronic portal imaging: report of AAPM Radiation Therapy Committee Task Group 58. Med Phys 2001;28:712-737. 29. Jaffray DA, Siewerdsen JH, Wong JW, et al. Flat-panel cone-beam computed tomography for image-guided radiation therapy. Int J Radiat Oncol Biol Phys 2002;53:1337-1349. 30. Mackie TR, Holmes T, Swerdloff S, et al. Tomotherapy: a new concept for the delivery of dynamic conformal radio- therapy. Med Phys 1993;20:1709-1719. 31. Langen KM, Jones DT. Organ motion and its management. Int J Radiat Oncol Biol Phys 2001;50:265-278. 32. Wulf J, Hadinger U, Oppitz U, et al. Stereotactic radiotherapy of extracranial targets: CT-simulation and accuracy of treatment in the stereotactic body frame. Radiother Oncol 2000;57:225-236. Correspondence address Authors: M. De Ridder, D. Verellen, N. Linthout, K. Tournel, S. Bral, G. Storme Department of radiotherapy, Oncology Center, University Hospital Brussels Please send all correspondence to: Prof. Dr. M. De Ridder Department of radiotherapy Oncology Center University Hospital Brussels Laarbeeklaan 101 B-1090 Brussels Belgium Tel: 0032 (0)2 477 6147 Fax: 0032 (0)2 477 6212 [email protected] Conflicts of interest: the authors have nothing to disclose and indicate no potential conflicts of interest. Call for contributions from readers Dear reader, Inspired by this issue of the Belgian Journal of Medical Oncology (BJMO)? You yourself can also play a part in this educational platform in Belgium! Consider submitting a contribution, such as a Letter-to-the-Editor, a case report, a review article, or other interesting manuscripts. The goal of the BJMO is to provide you with practical clearcut updates within the field of Oncology, Radiotherapy and adherent fields. The BJMO especially covers developments, which B E L G I A N J O U R N A L O F M E D I C A L have a clear impact on your activities in daily clinical practice such as diagnostic work-ups and disease management. The BJMO welcomes spontaneously submitted manuscripts as long as these comply with our editorial format and sections (see also : 'Instructions for Authors' in the back of this issue). We await any contribution with interest and also are looking forward to receiving any comments you might have to develop this journal in the future. The Editorial Board and Ariez Medical Publishing Ltd. O N C O L O G Y vol. 2 issue 5 - 2008 263