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1 Radiotherapy Physics Section, Radiotherapy Department, St Bartholomew's Hospital, 25 Bartholomew Close, West Smithfield, London EC1A 7BE and 2 Radiotherapy Department, St Bartholomew's Hospital, 25 Bartholomew Close, West Smithfield, London EC1A 7BE, UK
Correspondence: Dr P N Plowman
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Abstract |
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Introduction |
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The standard treatment for childhood medulloblastomas includes surgical resection, followed by moderate-dose radiotherapy to the craniospinal axis and then "boost" radiation therapy to the posterior fossa, with or without chemotherapy [1, 2]. Historically, a 33% 5-year survival rate with post-surgical radical radiotherapy has been reported [3]. A retrospective study by Merchant et al [4], which involved a review of 100 patients who were treated post-operatively with craniospinal radiation, revealed 5- and 10-year survival rates of 50% and 25%, respectively. More recently, Packer et al [5] concluded that for non-disseminated medulloblastoma, reduced dose craniospinal radiation with adjuvant chemotherapy results in better survival rates in children than delivering full dose radiotherapy with or without chemotherapy, with a progression-free survival of 86% at 3 years and 79% at 5 years. The addition of "platin"-based chemotherapy appears to contribute to these improved results. Treatment in adults can establish long-term survival rates of more than 50% of patients [6].
Patterns of treatment failure for medulloblastoma have been explored by Fukunaga-Johnson et al [7], who reported a 24% recurrence rate in 114 patients treated post-surgically with craniospinal radiotherapy, followed by a posterior fossa boost, and Merchant et al [4], who found a 64% failure rate of patients following the same treatment scheme. Both these studies showed that the most common site of relapse is the posterior fossa itself. This is also confirmed by Hughes et al [1] who reported that 78% of all recurrences in their study involved the posterior fossa. According to that study, local disease control in posterior fossa is directly related to radiation dose, in contrast to craniospinal axis radiotherapy.
Cranial radiotherapy, encompassing the inner ear, can induce sensorineural deafness in patients treated for medulloblastoma [8, 9]. This clinically important side-effect, which can cause difficulties in speech, language, communication and learning, must be considered during treatment planning. Characteristically, sensorineural hearing loss occurs 6–12 months following radiotherapy and can be irreversible. According to Kwong et al [10], the incidence of persistent sensorineural hearing loss in 132 patients followed up after radiotherapy for nasopharyngeal carcinoma was 24%. Higher frequencies in the audible range were more severely affected than lower frequencies. Both Huang [11] and Grau [9] established a dose–response relationship between radiation dose and effect on the hearing mechanism, and observed that children treated with a combination of radiotherapy and cisplatin therapy showed an increased rate of hearing loss. The severity of hearing loss with cisplatin is dose related, the clinical effect is bilateral and irreversible, and it is potentiated by radiotherapy prior to cisplatin therapy [12]. As cisplatin-based chemotherapy is now commonly part of therapy for medulloblastoma, this interactive toxicity on hearing is important.
The high incidence of sensorineural hearing loss and the likelihood of recurrence in the posterior fossa itself indicate the need for radiotherapy treatment plans which provide adequate coverage of the target volume whilst sparing the cochlea. Three-dimensional conformal radiotherapy (3D-CRT) has been shown to be superior to two-dimensional radiotherapy in conforming the high-dose volume closely to the planning target volume (PTV), without increasing doses to the inner ear structures (notably the cochlea and the vestibulocochlear nerve). Fukunaga-Johnson et al [2] compared conventional 2D parallel-opposed lateral field plans with a 3D-CRT cochlea-sparing technique, consisting of a pair of posterior oblique fields. Both techniques produced adequate target coverage, but the conformal technique reduced the dose to the cochlea to less than 70% of the prescribed dose, while the conventional plan delivered 100% of the prescribed dose to the cochlea. Paulino et al [13] also used conformal posterior oblique fields to reduce the dose to the cochlea to 50% of the prescribed dose. The addition of a vertex field increased the dose to the non-posterior fossa brain compared with two-field 3D-CRT, while further reducing the cochlea dose. Both conformal plans reduced the dose to the pituitary, at the cost of increased dose to the thyroid gland, pharynx, parotid gland and mandible. However, beam exit doses from multiple portals increase the integral dose to adjacent normal tissues and may lead to growth disturbances in children and increase the risk of secondary malignancies. Indeed, the potential usefulness of intensity-modulated radiation therapy (IMRT) in children may be adversely influenced by these factors. IMRT can increase the conformality of dose distributions, particularly for concave targets, and may improve tumour control while reducing normal tissue toxicity [14]. Huang et al [11] used IMRT to deliver boosts to the posterior fossa and the tumour bed; patients treated with IMRT developed less ototoxicity than patients treated with the conventional technique, even when the former received higher cisplatin doses. However, in addition to the elevated integral dose to normal tissues, IMRT often produces greater whole body doses because the longer irradiation times produce increased head scatter from the linear accelerator. These may both be of extra significance in paediatric radiation oncology. The technical challenges inherent in IMRT require greater resources for treatment planning, quality assurance and patient positioning. Further studies are required before conformal techniques, including IMRT, become standard therapy.
The current guidelines for radiotherapy of medulloblastoma state that all patients should receive radiotherapy to the craniospinal axis, followed by a boost to the posterior fossa. Modifying radiation beams to conform to the target volume has resulted in improved avoidance of critical structures around the posterior fossa. IMRT has shown promising results in other disease sites, such as prostate and head and neck cancers, by improving tumour targeting and reducing toxicity in normal tissues. The ability of IMRT to avoid organs-at-risk (OARs) while maintaining target dose homogeneity may be particularly useful for medulloblastoma treatment, as conformal radiotherapy preceding chemotherapy enables clinicians to increase the therapeutic dose of cisplatin without causing significant ototoxicity.
This study compares conventional 2D planning with 3D-CRT and IMRT planning in two paediatric and one adult posterior fossa treatment, to determine which technique reduces dose to inner ear structures. Treatments were compared for target coverage, their potential to reduce ototoxicity by limiting the dose to the cochlea, and for dose reduction in other OARs. The results are relevant to the treatment of medulloblastoma tumours that receive a posterior fossa boost, as well as CNS tumours which are treated by posterior fossa radiation.
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Methods |
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The CT scans were transferred to the treatment planning systems (ECLIPSE, Version 7.1.35; Varian Medical Systems, Palo Alto, CA) and the posterior fossa was contoured slice by slice. The posterior fossa borders were defined according to Drayer et al [15] and Carrie et al [16]. The PTV was constructed by adding a three-dimensional margin of 5 mm around the CTV. OARs – non-posterior fossa brain, pituitary, cochlea, eyes, optic nerves and cervical spinal cord – were also outlined.
Treatments were planned using three techniques (see Figure 1
): a standard two-dimensional plan; a conformal plan; and an IMRT plan. The standard plan, which constitutes the conventional 2D radiotherapy technique to treat the posterior fossa without cochlear sparing, consisted of two parallel-opposed lateral fields. The conformal plan consisted of a pair of wedged posterior oblique fields. The beam aperture was defined by the beam's-eye-view of the PTV, and a multileaf collimator (projected leaf width at isocentre was 5 mm) was used to shape the beams. The angles of the beams were arranged to cover the posterior fossa, while minimizing dose to the cochlea as much as possible. Four-field intensity-modulated plans were optimized with an inverse planning tool (HELIOS version 7.1.35; Varian Medical Systems). Treatments were planned with dynamic (sliding window) leaf motion.
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Plans were evaluated by comparison of dose distributions for the PTV and OARs. Dose–volume histograms (DVHs) were created for all outlined structures in each plan, and dose statistics were compared for the PTV and OARs.
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Results |
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shows the mean, maximum and minimum doses to the PTV for all treatment plans. On each plan, every slice that contained the PTV was examined to evaluate regions where the dose was less than 95%. In part, this is because the PTV extends into the build-up region of the beams, so doses will be reduced in this volume. Other regions where the dose was below 95% were adjacent to the brainstem, where medulloblastoma involvement is less likely. Consequently, the target coverage was deemed acceptable for all plans. The brain stem lies just inferior to the posterior clinoid and clivus, the pre-pontine space being small. The anterior surface of the brainstem could be underdosed in lateral portal radiotherapy techniques that attempt cocheal sparing. However, in the absence of three-dimensional conformal techniques, shaped lateral portals may be used. Any invasion of the brain stem by medulloblastoma is into the posterior/dorsal surface, making this procedure of less risk.
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. The conventional 2D technique (the standard method used in the UK for delivering the posterior fossa boost in medulloblastoma patients) produces greater doses in the inner ear structures compared with 3D-CRT and IMRT. Both cochlea received the target dose in this beam arrangement because they are entirely within the parallel opposed fields, and as a result, the minimum and maximum doses are very near the prescribed dose. For each patient, the conformal plans (both 3D-CRT and IMRT) delivered lower doses to the inner ear, without significantly compromising the dose distribution to the PTV. IMRT achieved the same level of cochlear sparing as conformal plans. However, for both these conformal plans, the mean dose to the cochlea was less than the dose delivered by the parallel-opposed beam arrangement (p<0.04).
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summarizes the mean doses to other OARs; typical DVHs for OARs are in Figure 2. 3D-CRT delivered the lowest dose to the non-posterior fossa brain (NPFB) in all plans. Although the doses to the optic nerves were acceptably low (less than 50 Gy) in all plans, the parallel-opposed pair plans reduced doses to the optic nerves better than the 3D-CRT and IMRT plans because of the beam directions (all beams in the conformal plans were directed anteriorly). Similarly, the conformal plans increased the lens doses relative to the parallel opposed beam arrangement – IMRT more that 3D-CRT (p<0.03) (see Table 3). However, in all cases, the lens dose was below the threshold for cataract induction (6–8 Gy) [17], even when the contribution from Phase I is included (our experience shows that this contribution is less than 4 Gy). Indeed, the values of the lens dose in Table 3 are very conservative, as the entire eye was outlined to avoid artefacts in the calculation of the lens DVH owing to the small volume of the lens. Doses to the anterior portion of the eye were less that the values recorded in Table 3.
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Discussion |
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The posterior fossa presents a suitable target for 3D-CRT, as it is easily immobilized and like adjacent OARs, readily identified on CT planning scans. 3D-CRT can conform the high dose volume closely to the PTV, without increasing doses to the inner ear structures, including the cochlea and the vestibulocochlear nerve. However, the small size of the cochleae and their position immediately adjacent to the posterior fossa, mean that day-to-day set-up variation introduces an uncertainty in the doses that are actually delivered to these OARs. This error could be exacerbated by the high dose gradients that can arise in IMRT, particularly in the presence of systemic set-up error. In this planning study, we have used 5 mm margins between the CTV and PTV, reflecting our experience (consistent with Fukunaga-Johnson et al [2]) with thermoplastic masks. Improved positioning reproducibility, which could further reduce dose to the cochlea, would likely require an invasive system, which is undesirable for the paediatric patient.
Fukunaga-Johnson et al [2] compared the dose distributions in the target volume (posterior fossa) and the cochlea for the conventional 2D technique (parallel-opposed lateral fields) and a 3D-CRT cochlear-sparing technique (a wedged pair of posterior oblique fields), as in this study. They found that, while the standard 2D technique delivered the prescribed dose to both cochlea, the 3D-CRT plan reduced the cochlear dose to <70% of the prescribed dose. Paulino et al [13] also demonstrated normal tissue sparing with conformal techniques. Lateral oblique wedged pairs, and a three-field treatment with a vertex field, delivered about 50% of the prescribed dose to both cochlea. The use of a vertex field improved cochlear sparing, at the cost of higher doses in the non-posterior fossa brain.
Both conformal plans in the study of Paulino et al [13] delivered a significant dose to the thyroid gland, pharynx, parotid gland, temporomandibular joint, dentition, mandible and anterior facial structures. In our IMRT plans, the oral cavity was occasionally within the 20% isodose. This may have significant effects on the development and function in those structures in children and even increase the risk of secondary malignancies, which, of course, the parallel opposed technique does not. This raises important issues related to the widespread adoption of modern conformal radiotherapy in paediatric radiation oncology. We emphasise, however, that our IMRT plans were optimized to reduce cochlear dose while maintaining PTV dose homogeneity. The inclusion in the optimization of other OARs may produce reduced doses in organs anterior to the posterior fossa, but perhaps at the expense of PTV uniformity.
Huang et al [11] compared conventional parallel-opposed fields with IMRT plans (the details of the IMRT delivery were unspecified). The IMRT plans also demonstrated cochlear sparing, delivering less than 70% of the prescribed dose to the cochlea. Doses to other OARs were not reported.
Our results reinforce the findings of these investigators, that conformal radiotherapy is able to substantially reduce doses to the cochlea during irradiation of the posterior fossa. Conformal plans reduce cochlear dose, largely due to the improved beam directions. The conventional parallel-opposed field arrangement unavoidably irradiates the inner ear to the target dose; the use of posterior oblique fields can exclude the cochlea from the fields, thereby reducing the dose. However, posterior fields increase exit dose in cranial structures anterior to the posterior fossa (e.g. the optic chiasm, the pituitary and the lens of the eye), particularly for the IMRT plans in this study. The use of more than two anteriorly-directed beams in the 3D-CRT plan will tend to increase dose in these structures, even if target dose homogeneity and cochlea sparing are maintained. Structures such as the cortex, the spinal cord, the lenses, the optic nerves and the pituitary, are particularly vulnerable to radiation injury when the posterior fossa is treated. Long-term neuropsychological disturbances, cataracts, stunted growth, and other hormonal disturbances from pituitary failure may result from increasing the doses to these structures. As a consequence, dose reduction in the cochlea does not necessarily recommend conformal planning for posterior fossa radiotherapy, unless it achieves acceptably low doses to other OARs compared with conventional radiotherapy.
The relatively high doses to the lenses (approaching the threshold for cataract induction) with the IMRT plans and the increased dose to anterior cranial structures must be taken into account when considering the most appropriate technique for a particular patient. Indeed, the morbidity caused by exceeding the tolerance dose to the lenses may be significant enough to recommend the conventional technique for posterior fossa treatment. However, in centres where 3D-CRT is available, it can deliver as low doses to the lenses and optic nerves as the conventional non-conformal planning.
Our study has shown that the increased cochlea-sparing effects provided by IMRT are minimal when compared with the 3D-CRT case. When limiting the field arrangement to coplanar beams, a minimum of four beams was required to meet treatment planning goals. While the use of as many as six posterior beams did improve target dose homogeneity, exit doses in the anterior half of the head were increased. The field-modulating properties of IMRT were not able to provide sufficient cochlear sparing when the beams entered the head through the cochlea; thus, beam entry was restricted to the posterior portion of the head.
Both the commonly available techniques of IMRT delivery (step-and-shoot and sliding-window) are inherently "monitor-unit (MU) inefficient"; that is, more beam-on time is required to deliver a given dose to the target volume, than with unmodulated beams. The increase in MU associated with IMRT results in greater head scatter in the linear accelerator, and therefore greater whole-body dose. This can have implications for the paediatric patient. Furthermore, IMRT is a very resource-consuming radiotherapy technique, as prescription times are increased due to the need for contouring OARs, treatment planning times are increased due to the time required for optimizing the beam fluences, and at present, the time needed for treatment validation because of the complex relationship between linac output and dose at a point in a modulated field. The implementation of such a resource-intensive technique (in particular, because of the associated staffing costs), may be beyond the means of many centres.
This study has not included the brainstem in the measurement and comparison of dose distributions. The tolerance dose of this structure depends on the volume included in the high dose region, as well as other variables like the number of surgical procedures at the base of the skull prior to radiation therapy and the presence of diabetes or hypertension, both of which reduce the tolerance limit. Doses less than 50 Gy have a very low risk of inducing long-term brainstem toxicity [18]; the target dose was less than this value, so the brainstem tolerance dose was not exceeded.
This study, and others, have demonstrated that conformal radiotherapy is better able to spare the cochlea than conventional 2D radiotherapy. The increased conformality usually associated with IMRT, does not, however, produce a substantial reduction in the dose to the dominant OAR (the cochlea) in posterior fossa radiotherapy, compared with 3D-CRT. This is due to the small size of the two OARs, their proximity to the target volume, and their location relative to the PTV and other OARs – notably the non-posterior fossa brain, the optic chiasm and the lenses. The difficulty of sparing the cochlea is reflected in the necessity of using an artificial OAR to ensure acceptable PTV dose homogeneity. 3D-CRT provides adequate target coverage, while reducing the dose to the cochlea, which should lead to a reduction in the incidence and severity of sensorineural hearing loss.
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Conclusions |
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3D-CRT plans consisting of shaped wedged posterior oblique fields were as successful as IMRT in sparing the cochlea, non-posterior fossa brain, cervical spinal cord and pituitary. IMRT delivered higher doses to anterior cranial structures such as the lens and the optic nerves. This study failed to establish that IMRT with coplanar beams is more beneficial than conformal wedged posterior oblique fields in sparing OARs. More complex IMRT plans, using non-coplanar beams, may provide improved conformality and tissue sparing, but this may be at the expense of increased beam-on times. The direction of any additional non-coplanar beam must be judiciously chosen, as this study has shown that the improved conformality of 3D-CRT and IMRT plans comes at the cost of increased dose to the front of the skull.
For centres unable to move immediately to 3D-CRT, the use of shaped lateral opposed fields may significantly lower the dose to the cochlea. In children, such simple use of parallel opposed portals, shaped with blocks or a multileaf collimator, does carry one advantage over 3D-CRT with posterior oblique beams: there is no problem with exit dose to structures other than the cochlea. The closeness of the cochlea to the PTV may result, however, in inadequate coverage of the PTV. Late sequelae in the parotid, dentition, or temporomandibular joint, due to the exit beams from the 3D-CRT beam arrangement, may prove important in the late follow-up years.
This study demonstrates the similar results achieved with 3D-CRT and IMRT for the target volume and dominant OAR (namely the cochlea), but highlights potential disadvantages of IMRT for paediatric work: greater integral dose to cranial structures resulting from multiple exit beams, and increased whole-body dose due to head scatter from the linac.
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Footnotes |
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Funding received from Cancer Research UK, West Wales Radiology Elective Bursaries, and the British Medical Association.
Received for publication December 23, 2002. Revision received October 31, 2003. Accepted for publication July 16, 2004.
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