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British Journal of Radiology (2004) 77, 88-96
© 2004 British Institute of Radiology
doi: 10.1259/bjr/84246820
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Review article

Clinical use of intensity-modulated radiotherapy: part I

M T Guerrero Urbano, MRCPI, FRCR and C M Nutting, MRCP, FRCR, MD

Radiotherapy Department and Head and Neck Unit, Institute of Cancer Research and Royal Marsden NHS Trust, London and Surrey, UK

Correspondence: Dr C Nutting, Head and Neck Unit, Royal Marsden NHS Trust, Fulham Road, London SW3 6JJ, UK


   Abstract
Top
 Abstract
Introduction
 Head and neck cancer
 Central nervous system tumours
 Lung cancer
 Conclusion
 References
 
Intensity-modulated radiotherapy (IMRT) is a novel conformal radiotherapy technique which is gaining increasing clinical use worldwide. This article aims to summarize the published data pertaining to clinical indications of this therapy for head and neck, central nervous system, and lung tumours. The main indications in head and neck cancer are parotid gland sparing and dose escalation to tumours close to organs at risk. For central nervous system tumours, IMRT has been used to reduce normal tissue radiation by more conformal dose distributions. To date, the majority of reports concern patients treated in the context of clinical trials, and for most tumour types longer term follow up of treated patients will be required to confirm the clinical benefits of IMRT.


   Introduction
Top
 Abstract
 Introduction
Head and neck cancer
 Central nervous system tumours
 Lung cancer
 Conclusion
 References
 
Intensity-modulated radiotherapy (IMRT) is a new development in three-dimensional conformal radiotherapy (3DCRT) combining several intensity-modulated beams to provide improved dose homogeneity and highly conformal dose distributions. This allows improved sparing of normal tissues in many tumour sites. Radiotherapy planning studies have confirmed the dosimetric advantages of IMRT over conventional or conformal techniques, and recently some studies evaluating its clinical impact have been published. These have mostly been reports of single-centre experience and some Phase I/II clinical studies that have reported high levels of tumour control and/or a reduction in normal tissue radiation toxicity. There is to date no randomized clinical trial data to prove conclusively an advantage of IMRT over conventional radiotherapy. Despite this, IMRT is rapidly becoming part of the standard treatment of patients with prostate and head and neck cancer, particularly in centres in the USA. This paper aims to discuss the clinical use of IMRT and to summarize the available clinical data. Due to the wealth of data available this review has been split into two parts. Part I covers tumours of the head and neck region, central nervous system, and lung. Part II discusses IMRT use for prostate, gynaecological, breast and gastrointestinal malignancies as well as other issues related to the clinical use of this new technique.


   Head and neck cancer
Top
 Abstract
 Introduction
 Head and neck cancer
Central nervous system tumours
 Lung cancer
 Conclusion
 References
 
Head and neck squamous cell carcinoma displays a clear radiation dose–response relationship, with both the probability of tumour control and the risk of radiation-induced normal tissue damage increasing with radiation dose. Treatment with radiotherapy is curative for many patients with localized disease, but with current radiation techniques, dose is limited by both acute and late side effects.

The anatomy of the head and neck region is very complex, with bony structures, soft tissues and air cavities all present in complicated arrangements, in the relatively small volume. The organs at risk (ORs) include spinal cord, brain stem, optic nerves, oesophagus and salivary glands that often lie very close to the target volume which commonly has an irregular concave shape. Partial reductions of the volume of normal tissue irradiated, such as those offered by 3DCRT, often do not reduce the risk of late toxicity. This is because the most critical OR (optic nerve, spinal cord, brain stem, optic chiasm) have in-series organization of functional subunits, where partial volume reductions do not significantly reduce the risk of radiotherapy-induced damage. Because of this, the dose to the planning target volume (PTV) sometimes has to be compromised. IMRT allows more conformal dose distributions, and plans can be produced with the aim of conformal avoidance of critical OR or dose escalation of the PTV.

The head and neck region can be readily immobilized, and accurate assessment of set up uncertainties can be made. This makes head and neck cancer an ideal model for IMRT because the tight dose gradients that can be achieved with IMRT can be used to avoid OR located close to the PTV.

Techniques
For locally advanced head and neck cancer, it has become popular to treat with simultaneous integrated boost (SIB) [1, 2] or simultaneous modulated accelerated radiotherapy (SMART) techniques [3]. These are characterized by the delivery of a different dose-per-fraction to different targets within the head and neck region. For example in the Cancer Research UK Parotid Sparing IMRT trial (PARSPORT), a dose of 2.17 Gy per fraction is delivered to the primary tumour site and involved lymph nodes, and 1.8 Gy per fraction to elective lymph node groups. After 30 fractions the primary tumour and involved lymph nodes have received a total of 65 Gy, and the elective lymph nodes 54 Gy (Figure 1Go).



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  		Figure 1. SMART boost technique used in PARSPORT trial showing a higher total dose (65 Gy) and dose per fraction (2.17 Gy) delivered to the primary tumour and involved nodes (red in 3D reconstruction and green colour wash) and lower total (54 Gy) dose and dose per fraction (1.8 Gy) to the elective nodes (purple in 3D reconstruction and orange colour wash).

 
The advantage of the SIB or SMART techniques is that the whole treatment course is planned only once, with savings in simulation, planning, delivery and verification time compared with conventional multiphase plans [4].

Radiobiologically, SIB and SMART techniques represent accelerated fractionation schedules that may reduce accelerated repopulation of tumour clonogens [5] and have shown improved tumour control [6]. Theoretically, the use of larger doses per fraction may be associated with increased late normal tissue radiation toxicity to structures with a low {alpha}/{beta} (e.g. nerves) within the high dose PTV. The long term follow up of patients will indicate if this is a significant clinical problem.

IMRT plans can produce concave dose distributions that include a midline primary tumour (e.g. larynx or thyroid) and lymph nodes on both sides of the neck. IMRT therefore can eliminate the use of electron fields to treat lymph nodes in the posterior triangle (level V). This reduces dose inhomogeneity in the PTV, and higher minimum doses offer the potential for improved tumour control [7].

Clinical results
Planning studies have shown potential dosimetric advantages of IMRT over conventional radiotherapy in head and neck tumours [8, 9]. Site specific planning studies have been performed for maxillary sinus [10–12], thyroid [13], parotid [14, 15] and other sites that will be discussed.

Butler et al [3] reported early follow up on 20 head and neck patients treated with a SMART boost technique delivering 2.4 Gy per fraction to the primary disease and metastatic lymph nodes and 2.0 Gy to the elective nodal regions (total doses of 60 Gy and 50 Gy, respectively, in 25 daily fractions). IMRT was delivered using 3 to 5 arcs (NOMOS PeacockTM system; MIMiC) matched to conventional anterior neck fields. They reported a 95% complete response rate and a 10% local recurrence rate. Radiation Therapy Oncology Group (RTOG) grade 3 acute mucositis was reported in 80% of patients; 45% reported moderate xerostomia with significant relief reported within 6 months (mean ipsilateral parotid gland dose was 23 Gy and contralateral was 21 Gy).

Parotid sparing IMRT
The ability of IMRT to produce dose distributions that may allow preservation of salivary tissue and reduction of xerostomia has been the subject of most head and neck trials (Figure 2Go). Parotid sparing IMRT was first used in Phase I/II studies performed at the University of Michigan with a forward-planned "step and shoot" IMRT technique using multiple non-coplanar photon beams and low-weighted electron fields to avoid the parotid gland [16, 17]. In 15 patients treated with this technique, IMRT improved the dose distribution and reduced dose inhomogeneity to the primary tumour and lymph node regions compared with standard three-field conformal plans. IMRT reduced the radiation dose to the contralateral parotid gland to 32% compared with 93% for the standard plans, the spared parotid glands receiving a mean dose of 19.9 Gy and recovering 63% of their pre-treatment stimulated salivary flow rates at 1 year. This compared with only a 3% recovery for treated parotid glands, which received 57.5 Gy [18, 19] (Table 1Go).



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  		Figure 2. Parotid gland sparing intensity-modulated radiotherapy (IMRT): a dose distribution to deliver a high dose to the target volume (blue contour and red colour wash) whilst sparing the parotid gland (pink contours) can be achieved with IMRT.

 

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  		Table 1. Mean stimulated salivary flow (± standard deviation) after parotid sparing intensity-modulated radiotherapy (IMRT)

 
An analysis of 88 patients treated with parotid-sparing IMRT allowed the correlation of radiotherapy dose with salivary flow measurements to produce dose–response curves for parotid gland function. A mean dose threshold was found for both stimulated (26 Gy) and unstimulated (24 Gy) saliva flow rates, such that glands receiving a mean dose below or equal to the threshold showed substantial preservation of the saliva flow following radiotherapy, which may continue to improve over time. By contrast, most glands receiving mean doses above the threshold produced little saliva and had no recovery over time [20].

A retrospective analysis of 28 patients with a spectrum of head and neck tumours treated with the MIMiC tomotherapy apparatus (NOMOS Corporation, Sewickley, PA) has been published from the Baylor College of Medicine [21]. 10 patients were treated for tumour recurrence after previous conventional radiotherapy, and in 18 patients IMRT was part of the primary treatment. A high degree of parotid sparing was demonstrated in these patients, with less than 20% of the total parotid volume receiving greater than 20 Gy. Long-term results are awaited.

The ability to spare the parotid gland is largely affected by its proximity to the PTV, and target volume definition is of critical importance. Van Asselen et al [22] showed a linear increase in the mean parotid dose with increasing clinical target volume (CTV)–PTV margin, emphasising the importance of immobilization and its effect on parotid gland sparing. 17 patients from the Mallinckrodt Institute received parotid sparing IMRT without a significant compromise of the dose delivered to the target volume. 27% (±8%) of parotid gland volumes were treated to more than 30 Gy and an average of 3.3% (±0.6%) of the target volume received less than 95% of the prescribed dose. This is mainly related to the steep dose gradient in the region where the target abuts the parotid gland [23].

Parotid sparing IMRT requires the mean dose to the spared gland to be less than 24–26 Gy. This has raised concern about a potential risk of tumour recurrence in the spared area. Two studies have evaluated the risk and location of locoregional recurrences in patients treated with parotid sparing IMRT [24, 25]. Locoregional recurrences were classified as within (in field), marginal or outside the IMRT treated volume. Out of a total of 184 evaluated patients, there were 3 marginal failures, only one of which was in the region adjacent to the spared parotid gland (Table 2Go). In both studies most recurrences occurred in areas of previous disease, within the radiotherapy treated area.


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  		Table 2. Locoregional recurrences following parotid sparing intensity-modulated radiotherapy (IMRT)

 
In the Dawson et al [24] study there were no failures in the tissue adjacent to the spared parotid gland. One patient recurred in the contralateral retropharyngeal nodes at the base of skull following post-operative radiotherapy for a T4N0 left tonsil/soft palate tumour. These nodes had not been defined as PTV, and their PTV definition protocol has subsequently been changed to include this area. The other marginal recurrence occurred in the ipsilateral submandibular nodes in a patient treated for a post-operatively recurrent squamous cell carcinoma (SCC) of the left alveolar ridge. Four patients developed in field recurrences in the jugulodigastric nodes with superior extensions in the ipsilateral neck. Recently consensus guidelines have been published suggesting the superior limit of level 2 nodes to be at the caudal edge of the transverse process of C1 [26]. In this study all target volumes were treated with IMRT. The median dose and range of RT delivered to the PTV for gross tumour, operative bed and subclinical disease were 70.4 Gy (66–76 Gy), 61.2 Gy (57.6–64 Gy), 50.4 Gy (46–54 Gy) and after a median follow up period of 27 months (6–60 months) locoregional control rate was 86%.

Chao et al [25] reported a 2 year actuarial locoregional control rate of 85% and an ultimate locoregional control rate after surgical salvage of 89%. In this study there was only one marginal recurrence, located in the region adjacent to the spared parotid gland. This was in a patient with a T3N0 piriform fossa tumour treated post-operatively where recurrence was in the level II nodal region adjacent to the spared parotid gland. Of the 11 in field recurrences, 9 were within the high dose CTV and 2 within the low dose CTV. It is interesting to note that five patients recurred in the lower neck, which had been treated in four patients with a matched anterior neck field and not treated in one patient. Matching of multiple IMRT fields to an anteroposterior (AP) lower-neck field is inherently associated with dose inhomogeneities as a result of the beams divergence and set up inaccuracies. In addition, dose distributions of AP neck fields are very inhomogeneous [27]. Areas of under-dosage using this technique could potentially be associated with the observed increased risk of recurrence in this area. Overall most of the recurrences occur within the high dose region, in agreement with conventional radiotherapy [28]. This suggests the existence within this volume of a subpopulation of cells resistant to radiation and/or chemotherapy. Tumour hypoxia has been shown to be associated with radio-resistance. The use of IMRT to selectively dose escalate hypoxic areas, in conjunction with hypoxic modifiers, is an interesting area of research that may lead to an improvement in the therapeutic ratio.

Currently, a phase I/II study of conformal and Intensity Modulated Radiotherapy for oropharyngeal cancer is being conducted under the RTOG (RTOG H-0022), and an international randomized study of parotid sparing IMRT versus conventional radiotherapy (PARSPORT) is underway in the UK, Belgium and the Netherlands.

Larynx/hypopharynx carcinoma
For patients with advanced cancer of the larynx and hypopharynx, the anatomical position of the tumour and regional lymph nodes relative to the spinal cord precludes the delivery of radiotherapy in a single phase. This requires the matching of photon and electron fields around the spinal cord, which leads to dose inhomogeneities close to the tumour or lymph nodes in the neck. With conventional radiotherapy, doses as low as 38 Gy have been observed within the nodal PTV, which is considerably less than those required to achieve tumour cell kill, and likely to contribute to local recurrence. Using IMRT, this treatment volume can be delivered in a single phase, without the need to match photons and electrons, resulting in more homogeneous dose distributions and spinal cord sparing to below 40 Gy [7] (Figure 3Go). This may give a higher probability of tumour control and allow the design of dose escalation studies. One such study is currently underway at the Royal Marsden Hospital where a SMART boost chemo-IMRT technique is used to treat locally advanced SCC of the larynx and hypopharynx. An initial report of acute toxicity showed a maximum incidence of grade 3 skin toxicity in 40% patients and grade 3 dysphagia and mucositis in 30% [29].



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  		Figure 3. The primary planning target volume (PTV) (in red) is shown encompassed by the 95% (green) isodose curve (63 Gy in 28 fractions). The elective PTV (neck nodes in pink) is treated to a lower dose (78% isodose curve in orange; 51.8 Gy in 28 fractions), whilst the spinal cord is kept below 40 Gy (60% isodose curve in pale blue).

 
Nasopharynx carcinoma
Tumours of the nasopharynx, which lie in close proximity to many ORs, commonly present with lymph node involvement requiring bilateral nodal irradiation. Local recurrence is the most common pattern of treatment failure, with rates between 32% and 60% for advanced tumours [30–32]. IMRT provides good coverage of the primary tumour and nodes, with the potential advantage of sparing the parotid glands and other ORs, and dose escalation.

23 patients with nasopharyngeal cancer were treated with IMRT at MSKCC. Plans provided higher PTV mean dose (77.3 Gy) compared with 3D CRT (74.6 Gy), improved PTV coverage and reduced dose to ORs (mean spinal cord dose reduced from 44 Gy to 34.5 Gy) [33].

The UCSF group reported 35 patients treated with IMRT with the goal to deliver a prescribed dose of 70 Gy to 95% or more of the gross target volume (GTV) (nasopharyngeal primary and retropharyngeal nodes) and 60 Gy to 95% or more of the CTV (entire nasopharynx, retropharyngeal lymph nodes, clivus, skull base, pterygoid fossae, parapharyngeal spaces, inferior sphenoid sinus and posterior third of the nasal cavity and maxillary sinuses). Concurrent chemotherapy was used in 91% and intracavitary brachytherapy in 32% of patients. Improved target coverage and dose escalation to a mean GTV dose of 75.8 Gy, with an average of 3% or less of the GTV receiving less than 95% of the prescribed dose were possible, and 100% local control rate at 2 years was reported. The average mean dose to the CTV was 71.2 Gy, with an average of 2% or less of the CTV receiving less than 95% of the prescribed dose. Serial ORs (brain stem, spinal cord, chiasm and optic nerves) were kept within tolerance and the average doses to 50% of the right and left parotids were 43.2 Gy and 41.0 Gy. All patients (100%) reported RTOG Grade 0 or 1 xerostomia 2 years after therapy [34]. In an update of their experience [35], with a total of 67 patients treated, they reported 4 year estimates of local, locoregional progression-free and metastasis-free survival of 97%, 98% and 66%, respectively. Overall dose–volume histogram (DVH) statistics showed a mean GTV dose of 74.5 Gy, a mean CTV dose of 68.7 Gy and average doses to 50% of the right and left parotid glands of 34.8 Gy and 33.9 Gy. It is important to note that in this study the authors stated that the GTV and CTV had an in-built PTV so as to account for patient set-up errors, and that the parapharyngeal spaces were included in the CTV. These spaces are in continuity with the deep lobe of the parotid gland and in our experience, in cases where the parapharyngeal space is target volume, and in particular the high dose target volume, achieving a mean parotid dose below 24 Gy is very difficult without compromising the dose to the target volume (Figure 4Go). Local control rates in this update remained very good, with one local recurrence at the primary site and one neck recurrence. There were, however, 17 distant metastases. Late grade >= 2 xerostomia was observed in 2% patients, but increased skin toxicity was observed. This was attributed to a bolus effect of the thermoplastic mask used for immobilization and the use of multiple tangential fields and the authors suggested the skin should be considered a sensitive structure for the inverse planning process [36]. This increase in toxicity has not been confirmed by other groups [37]. Levendag et al [38] suggested that stereotactic radiotherapy or IMRT provided better target coverage and sparing than brachytherapy for nasopharyngeal boost in patients with extensive residual disease after 46 Gy external beam radiotherapy (EBRT) and/or advanced (T3,4) tumours. Hsiung et al [39] found that increased vertical length and overlap of the target volume and the brain stem, spinal cord and/or eyes predicted greater dosimetric benefits with IMRT.



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  		Figure 4. The left parapharyngeal space is shown within the high dose planning target volume (PTV), in close proximity to the left parotid gland, treated beyond tolerance (mean dose above 24 Gy). On the right side, where the parapharyngeal space is not part of the high dose PTV, sparing can be more readily achieved.

 
Thyroid cancer
For patients with thyroid cancer considered at high risk of recurrence after thyroidectomy, external beam radiotherapy is used sometimes in addition to radioiodine. With present radiotherapy techniques 32% of patients do not obtain a complete response (CR), and of those attaining a CR, 39% relapse within the radiation portals, especially in the thyroid bed. IMRT has been shown to reduce the maximal spinal cord dose to 41.0 Gy and to improve significantly the coverage of the thyroid bed and nodal target volume (dose range 18.3%) using a five-equispaced field IMRT class solution when compared with conventional and 3DCRT (Figure 5Go) [13]. Dose escalation to the thyroid bed and/or nodal areas with IMRT may be able to improve local control and currently a phase I/II dose escalation study is underway at the Royal Marsden Hospital; patients with thyroid cancer, where external beam radiotherapy is indicated, receive 58.8 Gy in 28 fractions to the primary tumour bed and 50 Gy in 28 fractions to the elective nodal areas.



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  		Figure 5. Primary planning target volume (PTV) (thyroid bed and high risk nodal areas) encompassed by the 95% isodose curve (green), elective nodes by the 78% isodose and the spinal cord is kept below 40 Gy (60% isodose curve). Dose prescribed 58.8 Gy in 28 fractions to the primary PTV and 50 Gy in 28 fractions to the elective neck nodes.

 
Paranasal sinuses, aesthesioneuroblastoma
Tumours of this region are often advanced at presentation and invade adjacent structures, although lymph node involvement is generally uncommon. They lie in close proximity to many ORs (lens, retina, optic nerve and chiasm, pituitary gland) and irradiation to radical doses is often compromised due to this. Dose distribution with conventional techniques is often rather inhomogeneous, with areas of low dose that may contribute to local recurrence.

For maxillary sinus tumours, Adams et al [10] showed improved target coverage and a reduction in the doses to ORs with step and shoot IMRT when compared with 3DCRT and conventional RT (Table 3Go). A report of 11 patients with ethmoid sinus tumours treated post-operatively at the University of Ghent showed that dose escalation to 70 Gy with an optic nerve Dmax of 60 Gy was possible in 3 patients using IMRT [11]. A further report by this group [40] of 47 patients treated with post-operative radiotherapy for ethmoid sinus tumours, with median follow up of 32 months, revealed 3 year overall and disease free survival of 71% and 62%. 17 patients were treated with IMRT and prescribed doses ranged between 60 Gy and 70 Gy. Radiation induced severe dry eye syndrome and optic neuropathy were observed in 7 and 2, respectively, of the 47 cases, but none were in the group treated with IMRT.


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  		Table 3. Comparative dose–volume histogram statistics for maxillary sinus tumours [10]

 
Zabel et al [41] reported increased conformality and statistically significant sparing of the orbit and optic nerves (p<0.05) in 13 patients with aesthesioneuroblastoma treated to a dose of 60 Gy with inverse-planned IMRT when compared with CRT (Table 4Go). The authors reported an increased benefit of IMRT with larger and more complex shaped volumes.


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  		Table 4. Dose–volume histogram dose statistics for aesthesioneuroblastoma [41]

 
Optic nerves, chiasm, lens and retina show a positive correlation between maximum dose and complication rate [42, 43] and IMRT can potentially reduce the dose delivered to these organs, particularly in complex volumes that wrap around ORs, where a radical curative dose cannot be achieved without delivering a dose beyond tolerance to these.

Skull-base tumours
IMRT can improve target coverage of complex-shaped skull-base tumours, with a reduction in the dose delivered to the ORs, thereby allowing the delivery of higher doses, while the same ORs constraints can be met.

Uy et al [44] reported 40 patients with intracranial meningioma treated using IMRT with the NOMOS system. The median dose to the target volume was 53 Gy and mean dose to the optic nerve/chiasm 47 Gy with maximum doses up to 55 Gy. Cumulative 5 year local control was 93% and 2 patients progressed, one locally and one distally. Two patients experienced Grade 3 or higher late CNS toxicity with one possible treatment-related death. Pirzkall et al [45] demonstrated an improvement in target conformality and target coverage in 20 patients with benign skull-base meningiomas treated with IMRT by an average 10% and 36%, respectively, using 5–7 equispaced coplanar beams. At a median follow up of 36 months, they reported improvement of pre-existing neurological symptoms in 60% of patients and 2 patients developed late toxicity (pituitary dysfunction and visual loss).

Kuppersmith [46] reported the use of IMRT for the treatment of extensive and/or recurrent juvenile angiofibroma in three patients. Doses delivered to the tumour ranged from 34 Gy to 45 Gy and good conformality and sparing of normal tissues was achieved. Good radiological response was observed in all 3 cases with no endoscopic evidence of disease in two cases at 15 months and 40 months. No acute toxicity was reported and late toxicity was limited to one episode of epistaxis and persistent rhinitis in one patient.

Parotid tumours
A planning study of IMRT for parotid tumours [14] showed reduction of the radiation dose to the cochlea and oral cavity. Beam direction optimization software generated a novel 4 field ipsilateral coplanar anterior and posterior paired oblique fields (15°, 45°, 145° and 170°) [15] which had the potential to reduce mucositis and ipsilateral hearing loss. IMRT was also found to reduce the mean dose to the contralateral parotid gland and maximum doses to the brain and spinal cord [47].

Re-treatment
Locoregional relapse following high dose irradiation remains the most common form of treatment failure in head and neck cancer and it is often difficult to treat. Some cases can be salvaged by surgery, but for some sites, such as the nasopharynx, curative surgery is difficult or impossible, and re-irradiation may be preferable. Often this can be done with brachytherapy, which delivers highly conformal dose distributions with steep dose-gradients, but in some cases, access to position the sources is difficult and IMRT could play a role in treatment of these patients.

De Neve [48] reported three patients with nasopharynx, oropharynx and hypopharynx recurrences following radical radiotherapy, where IMRT allowed re-treatment of the tumour while avoiding overdose of the mandible, brainstem and spinal cord. Mean PTV doses were 63–73 Gy and maximum doses to the brain stem were 60–67 Gy and 21–34 Gy to the spinal cord. Re-irradiation of head and neck tumours with IMRT to doses between 30 Gy and 70 Gy with improved normal tissue sparing was has also been described by Chen et al [49].


   Central nervous system tumours
Top
 Abstract
 Introduction
 Head and neck cancer
 Central nervous system tumours
Lung cancer
 Conclusion
 References
 
Several studies have compared stereotactic radiotherapy with IMRT. Carol et al [50] reported a group of 13 (6 previously irradiated) patients treated using the Peacock system and showed an improved conformality index with 0–5% of ORs exceeding dose limits. Stereotactic radiotherapy was shown to be preferable for small targets but IMRT allowed more sparing of normal brain tissue in large (>4 cm) and moderately sized (2–3 cm) irregularly shaped targets [51, 52]. A small improvement in PTV coverage of convex tumours using the IMRT-tomotherapy method (Peacock system; Nomos Corporation) and a transaxial method of arc delivery was shown by Khoo et al [53]. However, due to the delivery method, there were higher doses to the optic nerves (11.2–11.6% higher) and lens (10.3–15.2%). Cardinale et al [54] evaluated different targets (ellipsoid, hemisphere and irregularly shaped with sizes 2–5.3 cm) planned with 5-arc linac stereotactic radiotherapy, 6-fixed non-coplanar custom blocked fields (3D) and intensity modulation using 6 non-coplanar beams and a mini-multileaf collimator. Arc stereotactic radiotherapy spared more normal brain tissue for ellipsoid lesions, but for the hemisphere and irregular tumour targets, dose conformity and high/low isodose normal brain volumes were more favourable with the IMRT technique.

Grant et al [55] reported one optic sheath meningioma treated to 50 Gy in 25 fractions and a craniopharyngioma treated to 50.4 Gy in 28 fractions, with the dose to the optic chiasm limited to 45 Gy. Fuss et al [56] reported 100% local control and hearing preservation rate (median follow up of 18.5 months) in 8 patients with acoustic neuromas treated with fractionated stereotactic IMRT. Stereotactic IMRT was also used in the treatment of 10 previously irradiated recurrent malignant gliomas by Voynov et al [57]. A median dose of 30 Gy at the 71% to 93% median isodose line was delivered and a median overall survival time of 10.1 months was reported.

Thilmann et al [58] reported improved target coverage and a 45% reduction in the volume of bowel receiving more than 40 Gy in a case of a partially resected sacral chordoma. IMRT has also been used to spare the spinal cord in the treatment of 8 patients with primary and metastatic tumours of the spine (6 re-irradiation cases) with no reported spinal cord complications [59]. Similar results were observed by Milker-Zabel et al [60] in 14 patients re-irradiated for recurrent spinal metastases.


   Lung cancer
Top
 Abstract
 Introduction
 Head and neck cancer
 Central nervous system tumours
 Lung cancer
Conclusion
 References
 
In locally advanced lung cancer, the use of high dose radiotherapy (RT) and/or concurrent chemo-RT is associated with significant pulmonary and oesophageal toxicity.

The Rotterdam Oncological Study Group [61] showed a reduction of 20.3% in the mean lung dose using 3D missing tissue compensators as well as a reduction in the total lung volume exceeding 20 Gy (V20). Derycke et al [62] compared a conventional three- or four-beam 3DCRT technique and two techniques involving, respectively, seven and five non-coplanar beam incidences with intensity modulation and showed an improvement both in TCP and lung NTCP for the IMRT plans, with no improvement with an increasing number of fields. Brugmans et al [63] showed that for lung cancer, a beam energy of 8 MV is more suitable than 18 MV and that the mean lung dose can be significantly reduced by decreasing the field sizes of conformal fields. Marnitz et al [64] showed a reduction of the irradiated lung volume using non-coplanar IMRT fields.

IMRT was initially reported, following radical pleurectomy/decortication for malignant mesothelioma, by Lee et al [65]. Tobler et al [66] reported an intensity modulated photon arc therapy technique that allows reduction of the lung dose and Forster et al and Ahamad et al [67, 68] reported 7 patients treated with adjuvant post-operative IMRT where good CTV coverage (50 Gy to 92–98% of the CTV) and normal tissue sparing were achieved. The most severe acute side effects reported were anorexia, N/V and dyspnoea (Figure 6Go).



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  		Figure 6. Intensity-modulated radiotherapy planned dose distribution for treatment of right pleura (reproduced with permission of Dr C Scrace).

 

   Conclusion
Top
 Abstract
 Introduction
 Head and neck cancer
 Central nervous system tumours
 Lung cancer
 Conclusion
References
 
The IMRT Collaborative working group suggested that direct testing of IMRT versus no IMRT is too reductionist [69]. This may be partly true, but a better dose distribution does not necessarily correlate with better clinical outcome or improved sparing associated with improved side effect profile and/or improvements in quality of life. Because of this, IMRT should be tested head to head with conventional radiotherapy techniques where possible. Some sites where an adequate dose is not achievable with conformal radiotherapy may be suitable for IMRT outside the context of a trial, as well as rare tumours where clinical trials are not feasible. The most exciting application of IMRT is to try and improve the therapeutic ratio by using its ability to spare normal tissues to evaluate modified fractionation schedules, dose escalation and chemoradiation.

Received for publication October 2, 2003. Accepted for publication December 1, 2003.


   References
Top
 Abstract
 Introduction
 Head and neck cancer
 Central nervous system tumours
 Lung cancer
 Conclusion
 References
 

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