Intensity Modulated
Radiotherapy in Cancer of the Larynx
M.T. Guerrero Urbano, C.H. Clark, M. Bidmead, D.P. Dearnaley, K.J. Harrington, C.M. Nutting
4
Contents
4.1 Introduction . . . 335
4.2 Clinical Problem, Patterns of Dissemination and Recurrence . . . 335
4.2.1 Glottis . . . 336
4.2.2 Supraglottis . . . 336
4.2.3 Subglottis . . . 336
4.3 Control Rates of Conventional RT . . . 336
4.4 Potential Benefits of IMRT and Indications . . . 337
4.5 Target Volume Delineation – OAR Definition . . . 338
4.5.1 Gross Tumor Volume . . . 338
4.5.2 Clinical Target Volume (CTV) . . . 338
High|Radical Dose CTV . . . 338
The Elective Neck CTV . . . 339
4.5.3 Planning Target Volume (PTV) . . . 339
4.5.4 Organs at Risk (OARs) and Planning Risk Volume (PRV) . . . 339
4.6 Planning, Dose Prescriptions and Optimization Strategies . . . 339
4.6.1 Prescription Dose Volume Histograms . . . 340
4.6.2 Field Parameters . . . 340
4.6.3 Additional Volumes . . . 341
4.6.4 Dose Constraints . . . 341
4.6.5 Optimization Strategies . . . 341
4.6.6 Analysis of Plans . . . 342
4.7 Clinical Experiences|Trials to Define the Role of IMRT 342 4.8 Future Directions . . . 342
References . . . 342
4.1 Introduction
The larynx is the organ of speech and tumours of this area and their treatment have a big impact on speech, swallowing and respiration. Most tumours arising in this area are squamous cell carcinomas that display 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 radia- tion techniques, dose is limited by both acute and late side effects. Locally advanced tumours are associated with poorer survival and manoeuvers introduced to improve results, such as accelerated radiotherapy frac- tionation and concomitant chemo-radiation schedules can result in significant morbidity.
Intensity-modulated radiotherapy (IMRT) is a new development in three-dimensional conformal radio- therapy (3DCRT) that by combining several beams of varying intensity achieves improved dose homogeneity with highly conformal dose distributions. In tumors of the larynx, the organs at risk (OAR) often lie very close to the target volume, which commonly has an irregular concave shape. Partial reductions of the volume of nor- mal tissue irradiated, such as those offered by 3DCRT, often do not reduce the risk of late toxicity. This is be- cause the slopes of the clinical dose-response curves are quite steep [19] and the most critical OAR (spinal cord) has in-series organization of functional subunits. This means that little extra dose can be given to the smaller high dose volumes resulting from the use of conformal techniques, without exceeding the complication rates produced when conventional tissue volumes are irra- diated to conventional dose-levels. 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 OAR or dose escalation of the PTV.
4.2 Clinical Problem, Patterns of Dissemination and Recurrence
The larynx is an important organ in vocal, swallow-
ing and respiratory functions. Alterations by disease or
by anti-cancer treatment will have a significant impact
on the patient’s quality of life. Most laryngeal squa-
mous cell carcinomas result from long-term exposure
to carcinogens, with tobacco smoking and alcohol be-
ing the two most important factors. These habits lead
to a number of concurrent medical problems, such as respiratory, cardiac, vascular and hepatic dysfunction that can all influence the patient’s ability to tolerate treatment.
The three anatomical laryngeal sub-sites (glottis, supraglottis and subglottis) have different lymphatic patterns: the true vocal cords have little or no lym- phatic drainage, the supraglottis has profuse lymphatic drainage to level II and III nodes and the subglottis drains to level III nodes. Laryngeal cancer is staged using the UICC TNM system [29].
4.2.1 Glottis
Glottic tumors are the commonest of all laryngeal can- cers, with most lesions located on the free edge of the anterior vocal cord. They tend to present early, as small alterations of the mucosal wave produce a persistent and early change in voice quality. Spread is initially mucosal, but later spread into the para-glottic space and under- lying tissues may affect vocal cord motion. The anterior commissure initially acts as a barrier to tumour spread, but once breached tumours can spread anteriorly into the pre-epiglottic space and/or laterally into the thy- roid cartilage. The likelihood of occult disease in the neck nodes for T1 tumours is deemed to be close to zero and very low (2–7%) for T2 tumours [46], with the risk increasing with higher T stage. Table 1 shows the anatomical distribution of cervical metastases from glottic cancers [58].
4.2.2 Supraglottis
Supraglottic lesions tend to present at a more advanced stage as symptoms (voice changes, referred ear pain and odynophagia) are produced late in the course of the dis- ease. Tumours arising in the supra-hyoid epiglottis can spread into the tongue base once the pre-epiglottic space has been invaded. Aryepiglottic fold cancers tend to fol- low a pattern similar to piriform sinus tumors, with a more diffuse local spread and a higher tendency to metastasize. Lymphatics in the supraglottis are abun-
Table 1.Anatomical distribution of cervical nodal metastases for glottic tumours
Level of involvement Larynx (glottic) Ipsilateral Contralateral
I 9.3% 0%
II (a + b) 50.5% 50%
III 21.5% 25%
IV 0% 0%
V 6.5% 0%
VI 12.3% 25%
Tomik et al.(2001)
Table 2.Anatomical distribution of cervical node metastases for supraglottic tumours
Level of involvement Larynx (supraglottic)
N0 45%a
N+ Ipsilateral Contralateral
a b a b
I 1% 10% 0% 0%
II (a + b) 38% 48% 12% 13%
III 26% 41% 5% 12%
IV 8% 7% 3% 4%
V 5% 5% 3% 1%
aLindberg (1972)bJohansen et al.(2002)
dant and the incidence of clinically positive nodes at the time of diagnosis is 55%, of which 16% are bilateral. The risk of nodal metastases increases with higher tumour stage: T1 63%, T2 70%, T3 79% and T4 73% [41]. The anatomical distribution of cervical node metastases in supraglottic tumors is shown in Table 2 [37, 41].
4.2.3 Subglottis
Primary subglottic carcinomas are rare [55] and most present late. Their spread is infiltrative with early inva- sion of the cricoid cartilage and cricothyroid membrane due to lack of tissue barriers. Often these tumours in- vade the vocal cords, making it difficult to determine where they are primary glottic tumours with subglottic spread or vice versa.
4.3 Control Rates of Conventional RT
Survival of laryngeal cancer sufferers decreases with in- creasing tumor stage. Early glottic cancer (T1-T2) is often successfully treated with radiation or surgery. Lo- cal control rates for T1 tumours following radiotherapy are close to 90%, increasing to 98% with surgical salvage [20]. Local control rates at five years with radiotherapy alone have been reported at 80% for T2 glottic tumors [44]. Larger doses per fraction [7,24] and hyperfraction- ated accelerated regimes with reduced overall treatment times [44] have been associated with response rates of 69–93% in T1 and T2 tumours. Response rates in patients with T3 and T4 glottic tumours are markedly poorer with local control rates of 53% after once-daily fractionation and 71% after twice-daily fractionation for T3 [45] and 56% for T4 tumors, with an overall five-year survival after radiotherapy and surgical salvage of 49%
for T4 N0 tumors [28].
For subglottic tumors, local control with radiother-
apy alone has been reported at 56% for all stages and
81.3% with surgical salvage for an overall five-year
survival rate of 50% [51].
Reported five-year disease specific survival rates for T1-T2 supraglottic tumors with radiation or surgery (primary or salvage) are similar, from 72 to 79% [56], but radiotherapy is associated with better organ func- tion and preservation of natural speech. The incidence of histopathologically positive nodes in clinically node negative patients treated with surgery alone has been reported as 30% [30] and the risk of occult contralat- eral metastases about 40% when an ipsilateral node was present [23]. Recurrence rates for the electively irra- diated neck have been reported as 3% [27]. Advanced supraglottic lesions respond less well to radiotherapy alone. Surgical management of these patients usually in- volves a total laryngectomy followed by post-operative radiotherapy to the primary site and the neck. In an attempt to preserve the larynx, accelerated radiother- apy and combination chemo-radiotherapy protocols have been evaluated reserving surgery for salvage [1, 4, 17, 21, 22, 32, 50, 52, 57]. A large multicentre ran- domised trial of laryngeal preservation showed two-year laryngeal preservation rates of 64% and two-year sur- vival 68% in both the surgical and radiation group [57].
A meta-analysis of chemotherapy added to the loco- regional treatment of head and neck cancer showed a statistically significant absolute improvement in sur- vival at five years of 8% with concomitant chemotherapy [52]. A meta-analysis of laryngeal preservation showed a non-statistically significant reduction in survival in patients with laryngeal tumours treated with organ- sparing approaches compared with those treated by surgery, but 23% of the patients who were alive at five years had preserved their larynx [52]. Other meta- analyses have also shown this benefit in local control and survival, but unfortunately, at the expense of signif- icant morbidity [1, 17]. Forastiere et al. [21] reported the results of a randomised trial comparing induction Cisplatin plus Fluorouracil followed by radiotherapy, ra- diotherapy with concomitant Cisplatin or radiotherapy alone (70 Gy in 35 daily fractions of 2 Gy to the primary and 50 Gy to the elective neck). Despite improved local control on the concomitant chemo-radiotherapy arm, there was no significant difference in overall survival between the three arms (75% at two years). However, 88% patients in the concomitant chemo-radiotherapy arm had maintained their larynx at median FU 3.8 years, vs 75% (p = 0. 005) in the neoadjuvant and RT arm and 70% (p < 0. 001) in the radiotherapy alone arm. These data translated to an absolute reduction in the rate of laryngectomy of 43%. Toxicity was more severe in the concomitant arm, with a marked increase of mucositis and esophageal toxicity.
Another approach to improve the therapeutic ratio is altered fractionation. There is evidence that pro- longation of overall treatment time is associated with reduced loco-regional disease-free survival [42] and that this is due to accelerated repopulation of tu- mor clonogens [61]. Fu et al. [22] reported an 8%
increase in loco-regional tumor control with a hyper- fractionated schedule or acceleration by concomitant boost technique (1.8 Gy/fraction/day, five days | week
and 1.5 Gy/fraction/day to a boost field as second daily treatment for the last 12 treatment days to 72 Gy | 42 fractions | 6 weeks) when compared with stan- dard fractionation (70 Gy in 35 fractions) or accelerated radiotherapy with a two-week treatment gap. Other randomized studies have also shown significantly im- proved tumour control and voice preservation with altered fractionation schedules [32, 50]. An ongoing meta-analysis of hyperfractionated | accelerated sched- ules has also shown increased responses at the expense of increased toxicity [4]. Both accelerated regimes and combination chemo-radiotherapy are associated with significant acute and potentially late toxicity.
4.4 Potential Benefits of IMRT and Indications
The main advantages of IMRT are more conformal and homogeneous dose distributions and sparing of nor- mal tissues. This is particularly relevant where matching fields are required in the context of conventional radio- therapy. Conventional radiotherapy for locally advanced tumours of the larynx usually involves two opposed lateral fields to include the primary tumour and up- per neck and a matched anterior (or an anterior and a posterior) neck field for the lower neck, including the stoma where appropriate. In patients where the posterior neck is electively treated, the anatomical po- sition of the tumor and regional lymph nodes relative to the spinal cord precludes the delivery of radiotherapy in a single phase, and requires the matching of pho- ton and electron fields to keep the spinal cord within the dose tolerance of 46–48 Gy. This leads to dose inhomogeneities close to the tumor or lymph nodes in the neck. With conventional radiotherapy planning studies have shown doses as low as 38 Gy within the nodal PTV [13]. These doses are considerably lower than those required to achieve tumor cell kill and may contribute to local recurrence. Using IMRT, treatment can be delivered in a single phase without the need to match photon | photon and | or photon | electron fields, re-
Fig. 1. (a),(b)Larynx and nodal dose distributions with IMRT. The red color denotes the 95– 105% of the primary dose. The orange color denotes the 95 –105% of the nodal dose. The pale blue is the cord tolerance
sulting in more homogeneous dose distributions and spinal cord sparing to below 40 Gy [13] (Fig. 1). These improved and more homogeneous dose distributions should theoretically be associated with a reduced risk of loco-regional recurrence. Additionally, the increased acute and late toxicity associated with accelerated ra- diotherapy and concomitant chemotherapy might also be reduced by virtue of reducing the radiation dose in normal tissues.
IMRT techniques such as simultaneous integrated boost (SIB) [48, 62] or simultaneous modulated ac- celerated radiotherapy (SMART) techniques [8], characterised by the delivery of a different dose-per- fraction to different targets within the head and neck region, have the radiobiological advantage of delivering both a higher total dose and a higher dose per fraction to the primary tumor and allow overall treatment times to be kept short [47].
Where bilateral nodal irradiation is indicated, radio- therapy using parallel-opposed fields is often associated with xerostomia, even when treatment is limited to an elective dose of 46–50 Gy. This adverse event is due to irradiation of substantial parts of both the parotid and submandibular salivary glands, located in close proxim- ity to level II neck nodes. IMRT allows unilateral and, in some cases (such as in N0 patients where the superior limit of level II nodes for the electively irradiated neck is set at the inferior aspect of the transverse process of C1 [25]), bilateral parotid gland sparing [5]. The pos- terior border of the submandibular gland represents the anterior boundary of level II neck nodes, making them difficult to spare even with IMRT.
Other potential future applications include selective dose escalation of biological gross tumor volumes and |
or hypoxic areas identified by PET scanning.
Early glottic cancer has good cure rates with ei- ther organ conserving surgical approaches or radiation therapy alone. The standard technique uses two parallel- opposed fields or two anterior oblique fields and often requires wedges to improve dose homogeneity and com- pensate for changes in the contour of the neck. Since there is no need for elective nodal irradiation, the field sizes required are very small and we feel that IMRT at its current stage of development has no role to play in the treatment of early laryngeal tumors.
4.5 Target Volume Delineation – OAR Definition
Accurate target volume definition and, therefore, knowl- edge of CT-based anatomy is essential when using IMRT to ensure all the involved areas and those at risk are in- cluded in the target volume. Consensus guidelines for the clinical target volume definition of the node negative neck have been recently published and were endorsed
by DAHANCA, EORTC, GORTEC, NCIC, RTOG [25].
A CT atlas of the head and neck region is available on the following websites:
• http://www.dshho.suite.dk/dahanca/guidelines.htlm
• http://groups.eortc.be/radio/EDUCATION.htm
• http://www.rtog.org/hnatlas/main.htm
There is, however, no such consensus applicable to target volume definition of the primary tumor and the involved and post-operative neck. ICRU 50 and 62 guide- lines provide the basis for defining the different target volumes [35, 36].
4.5.1 Gross Tumor Volume
The extent of the primary tumour and nodal Gross Tu- mor Volumes (GTV) can be difficult to determine, even on intravenous contrast-enhanced computed tomogra- phy (CT). Clinical assessment and careful examination under anaesthetic will help to assess the extent of disease. New imaging modalities (magnetic resonance imaging – MRI, positron emission tomography – PET and PET-CT) are currently being evaluated as an adjunct to conventional radiotherapy planning. MRI provides better soft tissue definition than CT and is helpful in determining invasion of the pre-epiglottic space | tongue base in supraglottic tumours and determining cartilage invasion. However, it is not suitable for radiotherapy planning alone due to lack of electron density informa- tion and inherent geometric inaccuracies.
4.5.2 Clinical Target Volume (CTV)
High
|
Radical Dose CTVThe primary CTV should encompass the primary and nodal GTVs and those areas at high risk of microscopic spread that will be treated to a radical dose. Chao et al.
[12] proposed a CTV, for patients who receive definitive IMRT, that encompassed the GTV and region adjacent but not directly involved, based on clinical findings and CT or MR imaging. Involved nodes were included with 2-cm margin.
As a general principle, uninvolved barriers to tumor spread, such as bone and fasciae and, of course, air can be excluded from this CTV. At our institution we add a minimum 1-cm margin to both the primary and nodal GTV, where no obvious anatomical barrier exists, to obtain a CTV.
Partial organ sparing in radiotherapy treatment of
early tumours is an exciting possibility, analogous
to partial pharyngectomy or partial laryngectomy. At
present, however, organ motion on swallowing and the
steep dose gradients created with IMRT in a small vol-
ume would make geographical miss a real possibility
and, therefore, it is not advised at present. We believe that
any reduction in the volume treated with radiotherapy should only be contemplated in the context of clinical studies, and suggest the inclusion of the entire larynx, in- cluding the thyroid cartilage, in the primary CTV. Other authors, however, have suggested the inclusion of only the ipsilateral hemi-hypopharynx and hemi-larynx in piriform fossa and lateral pharyngeal wall tumors [18].
For locally advanced tumours, at our institution, the entire larynx | hypopharynx complex is included within the radical CTV, from the tip of the epiglottis to the cricoid cartilage or 2 cm above or below the superior and inferior extent of the tumour, whichever is larger.
Clinical Target Volume in the Node Positive Neck
Where cervical nodes are involved, the probability of extra-capsular spread rises with increasing nodal size [2, 11, 31, 38], and this is linked to an increased proba- bility of recurrence [33]. Chao et al. advocated a 2-cm margin around involved nodes [12]. Where there is in- filtration of adjacent structures (i. e. muscle), it has been suggested to treat it in its entirety at least up to an elective dose [25].
The high dose CTV should be tailored to each spe- cific case, taking into consideration the tumor and nodal stage and involved anatomical areas. Considering the volume that would have been treated with conventional radiotherapy usually provides good guidance. Since IMRT is a new technique, it is advisable to be conser- vative to avoid increased recurrence rates in untreated areas.
The Postoperative Neck
In the post-operative patient the high dose CTV in- cludes any residual disease and | or the surgical bed of the primary tumour and involved nodes. Chao et al.
[12] advocated a postoperative CTV that encompassed the pre-operative GTV plus a 2-cm margin, including the resection bed of the area of soft tissue invasion by the tumor or metastatic nodes. The nodal volume will vary according to the type of neck dissection performed.
The Elective Neck CTV
Many studies suggest that the neck should be irradiated electively when the risk of occult cervical metastases is
>5% [3,9,10,41,43,54]. The consensus guidelines for the
node negative neck are an essential tool in delineating the elective CTV. However, the supraclavicular nodes, commonly treated in many UK centres, are not included.
Gregoire et al. [25] reported that few surgical dissections extend down to the clavicle and that they definitely do not reach the medial portion of the clavicle at the level of the sterno-clavicular joint. However there is some local variation in surgical practice, and in some centers neck dissections do extend down to this level.
4.5.3 Planning Target Volume (PTV)
A margin to account for patient motion, organ motion and set up inaccuracies is added to the CTV to obtain the PTV. Movement of the hypopharynx and larynx was estimated as 7 mm in the supero-inferior direction [59].
Different immobilization systems are in use in the head and neck region and an assessment of the degree of accuracy will determine the margin to be used in each centre. Such a study was performed at the Royal Marsden Hospital and a margin of 3 mm is added to obtain a PTV [34].
4.5.4 Organs at Risk (OARs) and Planning Risk Volume (PRV)
In this setting, the organs at risk are the spinal cord, brain stem, parotid glands, submandibular glands, mandible, and esophagus. A margin is added to spinal cord and brain stem to obtain a PRV according to ICRU 62 [36].
4.6 Planning, Dose Prescriptions and Optimization Strategies
The IMRT plans produced with SIB and SMART [8, 48, 62] techniques have concave dose distributions that include the midline primary tumor (e.g. larynx or hypopharynx) and lymph nodes on both sides of the neck, eliminating the use of electron fields to treat lymph nodes in the posterior triangle. This reduces dose inho- mogeneity in the PTV, and higher minimum doses offer the potential for improved tumor control [13]. This technique is used in a Phase I dose escalation study cur- rently conducted at the Royal Marsden Hospital, where
Fig. 2. SMART technique diagram
a dose of 2.25 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 28 frac- tions the primary tumor and involved lymph nodes have received a total of 63 Gy, and the elective lymph nodes 51.8 Gy (Fig. 2).
The advantage of the SIB or SMART techniques is that the whole treatment course is planned in a single phase, with savings in simulation, planning, delivery and verification time compared to conventional multi- phase plans [47]. Radiobiologically, SIB and SMART techniques represent accelerated fractionation sched- ules that may reduce accelerated repopulation of tumour clonogens and have shown improved tumour control.
Theoretically, the use of larger doses per fraction may be associated with increased late normal tissue radiation toxicity to structures with a low α|β ratio (e.g. peripheral or cranial nerves) within the high-dose PTV. Long-term follow up of patients will indicate if this is a significant clinical problem.
IMRT planning modules are now commonly available in treatment planning systems. The current planning techniques in IMRT can be divided into two methods, forward planned (i. e. the user determines the relative beam weights) and inverse planned (the user defines an ideal dose volume histogram and the optimization algo- rithm defines the beam weights). Forward planning can produce some excellent dose distributions [14, 16, 60];
however we will focus on inverse planning techniques.
4.6.1 Prescription Dose Volume Histograms
Inverse planning depends fundamentally on the initial design of the prescription dose-volume histogram. In order to do this it is essential to delineate a full 3D set of volumes of interest including all structures that will be analyzed in the plan approval (i. e. radical and elec- tive PTVs, spinal cord, parotid glands, etc.). Acceptable dose levels to be delivered to or avoided by those volumes must also be prescribed before the planning process can begin. Laryngeal cancer is treated at the Royal Mars- den Hospital within a phase I | II dose escalation study.
The dose levels are shown in Table 3. Examples of dose constraints used are 46 Gy for the spinal cord and 24 Gy mean dose to the parotids.
Table 3.Dose levels of phase I dose escalation IMRT study Current IMRT dose Dose escalation Larynx/
hypopharynx
Primary 63.0 Gy in 28# 67.2 Gy in 28#
tumour site (2.25 Gy per fraction) (2.4 Gy per fraction) Elective 51.8 Gy in 28# 56 Gy in 28#
nodal areas (1.85 Gy per fraction) (2 Gy per fraction)
Fig. 3. The IMRT beam arrangement consisting of two anterior and two posterior oblique fields and an anterior field which has been tilted by 10◦in the caudal direction
4.6.2 Field Parameters
The choice of beam parameters plays an important role in inverse planning. Gantry angle orientations can have significant effects on isodose shaping, normal tissue ori- entation and sparing of critical organs. This is especially true if a limited number of fields are used (e.g. 5). Most commercial inverse planning systems do not include gantry or collimator angle as part of the optimisation and therefore these basic field parameters need to be defined before the inverse planning begins. There has been much work done on finding class solutions for IMRT plans. This includes defining standard numbers of beams and their respective angles and energy as well as sets of predefined dose constraints. Initially the gen- eral consensus was that an odd number of equi-spaced beams was optimal and that more gantry angles was superior to fewer. However more recent work has sug- gested that for some sites equi-spaced fields may not be the optimal solution [6]. A modest number of appropri- ately selected beam orientations (Fig. 3) can sometimes provide dose distributions as satisfactory as those pro- duced by a large number of unselected equi-spaced orientations [13, 15, 49, 53]. Considerations regarding whether the beam is entering the patient through the couch or immobilization system should be taken into account as attenuation factors cannot always be easily applied, especially if they only apply to part of the field.
As with all 3D planning, gantry orientations that un-
necessarily irradiate tissue should be avoided, such as
entry through the shoulder for treatment of larynx tu-
mors (equi-spaced fields may produce this problem).
The position of the isocentre for individual patients will determine the exact angles available.
Non-coplanar beam orientations can help with avoid- ing treating through normal tissue. An anterior beam tilted in the cranial direction can irradiate the upper neck without passing through the anterior oral cavity.
This also causes the separation between the primary tar- get and parotid glands to increase, thus improving the sparing of the glands. A judicious choice of collimator angles can also improve sparing of the parotid glands by ensuring that the jaw is blocking the maximum amount of gland in the beam’s eye view of each field. Variation of collimator angle between the fields also ensures that any effects of tongue and groove are smeared out across the entire treated volume.
4.6.3 Additional Volumes
During the inverse planning process the optimisation algorithm will only attempt to cover or spare those vol- umes that have been fully outlined and that have a DVH to direct the optimisation process. It may be necessary to outline extra volumes where although strict dose spar- ing is not required it is still important to avoid “hot spots”.
Examples of this are the esophagus and the oral cav- ity, where it is preferable to reduce the dose if possible in order to avoid toxicity. A volume that does not strictly relate to the anatomy can be drawn so that a dose con- straint can be applied, with a relative low priority, that will help to avoid dose ‘overspill’ in this area. Such extra volumes can also be used to help shape the dose distri- butions. This is especially helpful where a lower number of gantry directions are used and therefore the shaping of the dose distributions is more difficult.
Expanded volumes (i. e. extra margins for planning purposes only) can be used to ensure coverage of targets.
Depending on the leaf widths and motions this may require differing margins in different directions. This
Fig. 4. A typical dose volume histogram for an IMRT treatment
technique can also be used to ensure sparing of organs at risk.
Target volumes which extend to near the skin surface can cause the planning system to increase the dose in a tangential field in order to compensate for the build- up of dose in a directly incident field and cause skin necrosis [39]. A clinical decision needs to be made as to the appropriate skin dose. Creation of a volume for planning purposes with the volume edited away from the skin surface [39] helps reduce excessive skin treatment.
The original volume can then be used for plan analysis.
4.6.4 Dose Constraints
The clinical prescription and dose limits form the goals of the inverse planning process. However, direct entry of these values into the optimization function does not always produce the optimal planning result. Inverse planning modules require dose volume points with as- sociated penalties or priorities. These often need to vary from the clinical prescription in order to take into account effects in the planning system such as the calcu- lation of the leaf motions and radiation leakage. If this occurs after the optimization process then user knowl- edge of the effects need to be included in the initial constraints such that the final solution is close to the clinical prescription.
4.6.5 Optimization Strategies
Some planning systems allow interaction with the op- timization function parameters during the process, whereas others use a more closed system. If interaction is available the changes to the dose | volume | priority values may be used to ‘drive’ the system towards the optimal solution. Gradient descent algorithms have a tendency to get stuck in a local minimum if the constraints are so
‘tight’ that only small steps may be taken in the optimiza-
tion iteration process. To avoid this, ‘looser’ constraints can be used in the early stages of the function, which are then ‘tightened’ as the function approaches the global minimum.
4.6.6 Analysis of Plans
Plans are analysed primarily based on comparison of the prescription constraints with the relevant points on the dose volume histogram (Fig. 4). Following this, dose dis- tributions are checked in transverse, sagittal and coronal slices, as untoward hot and cold spots may not be im- mediately obvious in the dose volume histogram due to the lack of spatial information.
4.7 Clinical Experiences | Trials to Define the Role of IMRT
There is little clinical experience in laryngeal cancer IMRT. The UCSF group reported having treated two la- rynx patients as part of their overall experience with head and neck IMRT [40]. Patients with stage T2–4, N1–3, M0 squamous cell carcinoma of the larynx and hypopharynx are currently being recruited into a phase I dose escalation study at the Royal Marsden Hospital.
The dose levels are shown on Table 3 and patients receive concomitant Cisplatin, 100 mg/m
2on weeks 1 and 5. To date 15 patients have been treated to the first dose level and 5 patients have been recruited to the dose escalated level. A report of toxicity following treatment of the first 11 larynx | hypopharynx patients with median follow up
Fig. 5. Typical skin reaction
of 6 months (range 2–24) showed no grade 4 toxicity.
Mean PTV1 D95 was 60.3 Gy (range 57.8–61.42) and mean PTV 2 | 3 D95 48.14 Gy (range 47.2–49.1). Thirty seven percent of all patients developed skin toxicity grade 3. A typical pattern of widespread erythema with dry and | or moist desquamation over the neck creases was observed (Fig. 5). Half of the patients required na- sogastric or gastrostomy tube feeding. Most patients experienced mucositis and pain grades 1–2, with 44%
reporting grade 3. A positive correlation was found with maximum oral cavity dose (R = 0. 7, 95% CI 0.3–0.9;
p
= 0. 002) [26].
4.8 Future Directions
IMRT has a defined role in improving the therapeutic ra- tio in laryngeal cancer. Its ability to spare normal tissues can be exploited to design studies that evaluate conven- tional and accelerated fractionation radiation regimes in conjunction with concomitant chemotherapy, hypoxic sensitisers, biological agents (i. e. Iressa) and | or gene
therapy. Another exciting area of study is the boosting of hypoxic areas and | or biological gross tumour vol- umes as identified on PET scanning and re-treatment of small recurrences.
The increasing use of IMRT in the clinic will provide us with new data which will allow us to maximise its po- tential with the dual aim of improving patient’s survival and quality of life.
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