Comparison of forward planned conformal radiation ... - BIR Publications

The British Journal of Radiology, 75 (2002), 356–361

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2002 The British Institute of Radiology

Comparison of forward planned conformal radiation therapy and inverse planned intensity modulated radiation therapy for esthesioneuroblastoma 1

A ZABEL, MD, 1C THILMANN, MD, 1I ZUNA, PhD, 2W SCHLEGEL, PhD, 3 M WANNENMACHER, MD and 1,3J DEBUS, MD, PhD Departments of 1Radiotherapy and 2Medical Physics, German Cancer Research Center, INF280, 69120 Heidelberg and 3Department of Radiotherapy, University of Heidelberg, INF400, 69120 Heidelberg, Germany

Abstract. The purpose of this study was to compare dose distribution of inverse planned intensity modulated radiation therapy (IMRT) with that of conformal radiation therapy (SCRT) in the treatment of esthesioneuroblastoma, and to report initial clinical results. 13 patients with esthesioneuroblastoma were planned both with IMRT and SCRT using complete threedimensional data sets. A target dose of 60 Gy was prescribed. We performed a detailed dose volume histogram analysis. Dose coverage was equal in both plans while dose distribution was more conformal to the target volume with IMRT. Mean and maximum dose of the brain stem, chiasm, optic nerves and orbits were lower using IMRT than SCRT. The reduction was significant regarding orbit and optic nerve (p,0.05). IMRT was superior in sparing of organs at risk compared with SCRT. The additional sparing by IMRT was positively correlated to the size of the target volume, which was evident with target volumes above 200 cm3. Treatment time was approximately 20 minutes per fraction using IMRT compared with 15 minutes per fraction using SCRT. We conclude that IMRT is both feasible and a valuable tool for more conformal dose distribution in the treatment of esthesioneuroblastoma and to spare organs at risk that are in critical relationship to the tumour. This advantage could be seen especially well in complex shaped target volumes above 200 cm3. Thus, using IMRT, risk of complications may be minimized and local tumour control may be increased. Radiotherapy of esthesioneuroblastoma is challenging owing to close proximity of the tumour to radiosensitive structures such as eyes, ocular adnexa and brain stem. The limiting factor in dose delivery is the tolerance of normal tissue. The goal of radiotherapy is to maximize radiation dose to the tumour while keeping the dose to the surrounding normal tissues below their respective tolerance doses. Conventional 3-field technique consists of a wedged anterior field and two wedged lateral fields [1]. This approach results in high exposure of structures of the optical apparatus to radiation. Parts of the optic nerves or chiasm incidentally receive doses that approximate to the prescribed target dose. Additional use of a shield block for the eyes is critical because the lateral fields do not cover the anterior parts of the tumour and resulting target dose inhomogeneity is high. To reduce complications of irradiation in the nasal and orbital area, sophisticated

treatment planning in esthesioneuroblastoma radiotherapy is recommended [2–4]. Stereotactically guided conformal radiation therapy (SCRT) offers the prospect of improving dose coverage of the tumour volume and decreasing the risk of normal tissue complications, therefore allowing an increase in tumour dose to levels above those given with conventional techniques [5]. Between 1997 and 2001 we have treated more than 200 patients with intensity modulated radiation therapy (IMRT). This paper analyses the role of inverse planned IMRT as a new tool in radiotherapy for esthesioneuroblastoma. For each patient, an IMRT plan as well as a SCRT plan was calculated and compared. We performed a detailed dose volume histogram (DVH) analysis, with comparison of dose coverage and dose homogeneity of the target as well as volume above the respective clinical tolerance doses of normal tissues, mean dose and maximum dose.

Received 11 May 2001 and in revised form 31 July 2001, accepted 20 August 2001.

Methods and materials

Address correspondence to Dr Angelika Zabel, Abt. Klinische Forschungseinheit Strahlentherapeutische Onkologie, Deutsches Krebsforschungszentrum, INF 280, 69120 Heidelberg, Germany.

The complete three-dimensional (3D) data sets of 13 consecutive patients with esthesioneuroblastoma who underwent fractionated stereotactic

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Intensity modulated radiotherapy for esthesioneuroblastoma

3D-planned radiotherapy in our institution were used. Nine patients were treated using SCRT and four patients using inverse planned IMRT. Retrospectively, we performed an additional IMRT or SCRT plan in each case. Treatment planning was based on MRI and CT scans of the head in individual mask fixation [6] under stereotactic guidance. The patient-specific mask was attached to the CT/MRI couch for planning and then to the treatment couch. A non-invasive stereotactic frame with an external coordinate system was fixed to the mask to mark the isocenter. Volumes of interest (VOIs) were created using the manual segmentation module TOMAS, which is part of the 3D radiotherapy planning system Voxelplan (DKFZ, Heidelberg, Germany) [7]. The target was defined depending on pre-operative tumour extension, including nasal cavity and adjacent sinuses in 10 cases, and depending on only macroscopic tumour in three cases. Chiasm, right and left optic nerves, the lacrimal glands, lenses and orbits as well as brain stem, were defined as organs at risk (OAR). IMRT planning was performed using the inverse planning programm KONRAD [8], which was developed at the German Cancer Research Center, Heidelberg, Germany. A median of 7 (range 5–9) non-coplanar and coplanar beams were defined depending on the complexity of the target volume. We used a class solution of parameters and beams for the first approach of a treatment plan in each patient (Table 1). When this approach resulted in an unsatisfactory dose distribution we individualized the organ constrains and/or number of beams. We used a commercial multileaf collimator in a ‘‘step and shoot’’ technique [9]. SCRT was performed using the virtual planning module VIRTUOS within Voxelplan [7]. We used a median of 4 (range 3–5) irregularly shaped noncoplanar beams per treatment plan. The portals were optimized using a beam’s eye view technique. Beam shaping was done with a manually driven midsize multileaf collimator. Dose prescription was 60 Gy in both treatment plans. The dose was prescribed to the median

dose of the planning treatment volume (PTV) on the DVH. The 90% isodose was chosen to enclose the PTV. This approach was used for all IMRT dose prescriptions because it is robust to local under or overdosages within the PTV. Consequently dose was prescribed to a point on the DVH rather than a point within the dose distribution. This approach does not follow ICRU 50 definitions [10], however, it has recently been shown that prescription to median dose is correlated to clinical outcome [11]. For comparison, 3D dose distribution, DVHs as well as percentage above respective clinical tolerance doses and below 90% isodoses and mean and maximum doses for all VOIs, were calculated for the IMRT and the SCRT plan of each patient. Mean and maximum doses were chosen for evaluation because they have been shown to correlate with complication rates in normal tissues [12, 13]. We used the sign rank test for statistical evaluation. The level of significance was chosen to be p ,0.05.

Results The mean treatment volume was 172.5 cm3 (range 13.1–330.0 cm3). Dose coverage of the target was equal in both treatment plans. The histogram statistics for the target as median values of all patients are shown in Table 2. The Table 2. Histogram statistics for the target volume. All data as median values of all patients. The hotspots (volume.107% isodose) are located within the target volume in both treatment plans SCRT

IMRT

9 25 3 59.2 32.5 66.3

8 22 8 59.6 35.2 71.0

% volume,90% isodose % volume,95% isodose % volume.107% isodose Mean dose (Gy) Minimum dose (Gy) Maximum dose (Gy)

SCRT, conformal radiation therapy; IMRT, intensity modulated radiation therapy.

Table 1. Class solution for intensity modulated radiation therapy planning for esthesioneuroblastoma. These were individualized as necessary Beam No.

1 2 3 4 5 6 7

Beam direction

Organ constrains

Gantry

Couch

Volume

Priority

Max. dose

Penalty

Min. dose

15 ˚ 60 ˚ 79 ˚ 124 ˚ 236 ˚ 286 ˚ 330 ˚

90 ˚ 90 ˚ 0˚ 0˚ 0˚ 0˚ 90 ˚

Target Chiasm Optic nerves Brain stem Orbits

1 2 3 4 5

60 45 40 45 10

200 200 400 200 300

60 0 0 0 0

Gy Gy Gy Gy Gy

Gy Gy Gy Gy Gy

Max., maximum; Min., minimum.


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A Zabel, C Thilmann, I Zuna et al Table 3. Mean and maximum (Max.) dose (Gy) of organs at risk (OAR) as median values of all patients

Figure 1. Axial dose distribution of a patient for conformal radiation therapy (left) and intensity modulated radiation therapy (IMRT) (right) at the same level. The isodose lines are 10%, 20%, 50%, 60%, 80% and 90%. The orange colour-wash represents the 60–80% isodoses. Dose distribution is more conformal to the planning treatment volume (red line), and sparing of orbital structures is improved, using IMRT.

volume receiving more than 107% of the prescribed target dose was higher using IMRT, 8% compared with 3% using SCRT. These hot spots are located within the target volume and are frequently seen in IMRT. The volume below the 95% isodose was comparable for both treatment plans. Minimum doses in both plans were located at the periphery of the PTV and were determined by either a small volume or just one point in the dose distribution. Dose distribution was more conformal to the target using IMRT (Figure 1). The percentage of critical structures receiving more than clinically relevant doses could be reduced using IMRT (Figure 2). Table 3 illustrates the mean and maximum doses, as median values, for OAR of the two different plans for all patients. Mean and maximum doses to OAR could be reduced using IMRT. For example, the

Figure 2. Percentage of organs at risk (OAR) receiving more than clinically relevant doses as box-whisker plots for all patients. The volume of OAR receiving more than their respective tolerance doses could be reduced using intensity modulated radiation therapy. 358

OAR

SCRT IMRT SCRT IMRT Mean Mean Max. Max. dose dose dose dose

Chiasm Right orbit Right lens Left orbit Left lens Right lacrimal gland Left lacrimal gland Right optic nerve Left optic nerve Brain stem

30.6 16.8 10.2 13.8 7.8 13.8 10.8 39.6 39.6 18

24.6 12 9.6 11.4 7.8 12.6 8.4 33.6 31.2* 14.4

*significant, p,0.05. SCRT, conformal radiation therapy; modulated radiation therapy.

40.8 47.4 12.6 45 13.8 22.8 17.4 52.2 54 41.4

37.2 33 10.8 28.8* 9 17.4 15 48.6* 45 36.6

IMRT,

intensity

chiasm was exposed to 41% of the mean prescribed target dose with IMRT compared with 51% with SCRT, the right optic nerve 56% with IMRT compared with 66% SCRT, the left optic nerve 52% with IMRT compared with 66% with SCRT and the brain stem 24% with IMRT compared with 30% with SCRT. These differences were significant (p,0.05) regarding mean dose of the left optic nerve and maximum dose of the right optic nerve and left orbit. Figure 3 shows an exemplary DVH of a patient for both treatment plans regarding the target, left orbit, left lens and left optic nerve. Regarding each single patient, IMRT was significantly superior to SCRT in sparing of OAR in 9 of 13 cases. This finding was positively

Figure 3. Example of a typical dose volume histogram of a patient for intensity modulated radiation therapy (IMRT) (back) and conformal radiation therapy (SCRT) (grey) regarding the target, left orbit, left lens and left optic nerve. Target coverage is equal in both plans. IMRT was always superior to SCRT in sparing organs at risk. The British Journal of Radiology, April 2002

Intensity modulated radiotherapy for esthesioneuroblastoma

correlated to the size of the target volume. IMRT was superior in median treatment volumes larger than 215 cm3. In smaller target volumes IMRT and SCRT achieved similar results. IMRT was especially superior to SCRT in cases where parts of the target volume were in close relationship to OAR. Four patients with esthesioneuroblastoma had already been treated with IMRT in our institution. These IMRT plans used a median of 8 beams (range 7–9), a median of 81 subsegments (range 62–107) and a median of 999 total monitor units (60 Gy) per treatment plan. Median overall treatment time was 20 min per fraction. The corresponding SCRT plans, with a median of 4 beams, would have used a median of 222 total monitor units (median of 57 monitor units per beam). Treatment time could be estimated to 15 min per fraction. Regarding the four patients treated with IMRT, we observed no local failures after a median followup of 10 months (range 7–16 months). No severe late effects (common toxicity criteria (CTC) .II ˚) of irradiation were seen. Local erythema (CTC I ˚) and mild epiphora were seen in all four patients. We observed no clinically significant late toxicity in these patients thus far.

Discussion Our data indicate that IMRT is superior to forward-planned SCRT techniques in the treatment of esthesioneuroblastoma, especially in cases with large and complex shaped tumour volumes in critical proximity to OAR. SCRT is capable of improving dose coverage of the tumour volume and decreasing the risk of normal tissue complications and therefore allows an increase in tumour dose to levels above those given with conventional techniques [5]. New 3D planning techniques, such as inversely planned IMRT, are capable of conforming the high dose region more closely to the target, thus reducing the volume of normal tissue receiving a high dose. Our evaluation showed the ability of IMRT to escalate the dose to the target volume to a higher extent than SCRT while sparing surrounding radiosensitive normal tissue. The percentage of OAR receiving clinically relevant doses, as well as the mean and maximum doses, could be reduced using IMRT. Therefore, the risk of radiation-induced late effects in normal tissues might be reduced, or local tumour control might be increased, by dose escalation. Martel et al [12] described dose volume information and normal tissue complication probability calculations for the optical apparatus. A positive correlation between maximum dose The British Journal of Radiology, April 2002

and complication rate has been shown for optic nerves and chiasm. Cataract and late retinal complications, such as retinopathy, glaucoma and central retinal artery occlusion, are well known adverse effects of irradiation in the nasal and orbital area, with steep dose–effect relationships. In Takeda et al’s evaluation [14], the rate of eye complication in patients whose eyes were irradiated with 50 Gy or more was 38.1%. The incidence of radiation retinopathy was 44% and the incidence of neovascular glaucoma 14%. Sophisticated treatment planning is recommended in radiotherapy of esthesioneuroblastoma in order to reduce these complications [2, 3]. Brizel et al [13] compared conventional vs conformal beam orientations in paranasal sinus malignancies and found reductions of normal tissue receiving more than 80% of the average target dose, maximum doses and mean normal tissue complication probabilities to the eyes, optic nerves and chiasm with conformal planning. The goal of radiotherapy is to achieve dose homogeneity without underdosage within the target volume, with low risk of adverse reactions of surrounding radiosensitive structures. Roa et al [5] showed that CT-based 3D radiotherapy is beneficial in minimizing the risk of eye complications in the management of advanced paranasal sinus neoplasm. Further gains in dose conformity and reduction of exposure of non-target structures may be achieved with IMRT. Early clinical results have been published for head and neck cancer [15, 16] that show IMRT is able to improve dose distribution and dose conformity of the target. IMRT has been shown to be effective in preserving substantial major salivary gland function without compromizing target coverage by reducing mean dose and volume of high doses in non-involved tissue. These findings in salivary glands may be transferred to lacrimal glands as well. In our analysis, target coverage using IMRT was equal to that using SCRT. The maximum dose delivered to OAR as a limiting factor owing to the risk of developing complications was lower with IMRT than with SCRT, and dose distribution was more conformal to the target volume using IMRT compared with SCRT. Regarding single patients, a positive correlation could be seen between size of the treatment volume and the extent of sparing OAR with both plans. IMRT was superior in median treatment volumes of 215 cm3 whereas SCRT was equivalent to IMRT in smaller treatment volumes. Conversely, there may be cases with small treatment volumes of complex shape, e.g. when the tumour wraps around OAR, in which IMRT is capable of delivering a concave dose distribution in contrast to SCRT [17]. The superiority of IMRT may be attributed not only to the fact that an increased number of beams is used. We have 359

A Zabel, C Thilmann, I Zuna et al

recently shown that IMRT is also superior to SCRT when identical beam numbers and directions are chosen [18]. Radiotherapy is an important component in the management of malignant tumour to prevent local recurrences [19]. In the evaluation of Eden et al, therapy failed 55% of 40 patients, and 68% of these failures were locoregional [20]. Evidence exists that local tumour control improves survival rates, therefore more aggressive treatment is justified [21]. Koka et al [22] concluded that initial multimodality treatment offers better survival and disease-free interval. Distant metastases significantly affected survival. The 3-year overall survival in patients with metastases was 6% compared with 90% in patients without metastases. Furthermore, metastases alone occurred in 25% of patients, whereas it was associated with local or regional failure in 75%. Achieving local control therefore is essential. A lack of sufficient local tumour control in radiotherapy may be attributed to insufficient dose coverage of the target or dose inhomogeneity. We expect substantial improvement of clinical outcome by using IMRT for esthesioneuroblastoma because dose distributions are superior and dose response has been documented. Depending on the number of subsegments, treatment time using IMRT (20 min per fraction) was only negligibly longer than it would have been using SCRT (15 min per fraction) in the four patients already treated with IMRT in our institution.

Conclusion The advantage of 3D radiotherapy planning in esthesioneuroblastoma is apparent in stereotactically guided radiotherapy techniques compared with combined ventro–dorsal and lateral irradiation techniques regarding dose homogeneity and conformity, as well as sparing of OAR. Compared with SCRT, inverse treatment planning achieves an even more conformal dose distribution of target structures, while OAR are spared to a greater extent, especially in complex shaped target volumes above 200 cm3. This may lead to an increase of local tumour control and avoids complications of high-dose radiation therapy of OAR in critical relationship to the tumour, such as in the nasal and orbital area. IMRT has clear advantages in selected clinical cases when no satisfactory dose distribution or sparing of OAR can be achieved with SCRT. With increasing experience, the time for IMRT treatment planning could be shortened. The time taken to deliver IMRT for esthesioneuroblastoma is comparable to that of previously published complex 3D radiotherapy treatment techniques [23]. 360

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