Intensity Modulated Neutron Radiotherapy for the Treatment of Adenocarcinoma of the Prostate

Int. J. Radiation Oncology Biol. Phys., Vol. 68, No. 5, pp. 1546–1556, 2007 Copyright Ó 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter

doi:10.1016/j.ijrobp.2007.04.040

PHYSICS CONTRIBUTION

INTENSITY MODULATED NEUTRON RADIOTHERAPY FOR THE TREATMENT OF ADENOCARCINOMA OF THE PROSTATE LAKSHMI SANTANAM, PH.D.,* TONY HE, PH.D.,y MARK YUDELEV, PH.D.,z JEFFREY D. FORMAN, M.D.,z COLIN G. ORTON, PH.D.,z FRANK VANDEN HEUVEL, PH.D.,k RICHARD L. MAUGHAN, PH.D.,{ AND JAY BURMEISTER, PH.D.z * Department of Radiation Oncology, Washington University, St. Louis, MO; y Oregon Health and Science University, Portland, OR; z Wayne State University, Karmanos Cancer Institute, Detroit, MI; k University Hospitals K.U. Leuven, Leuven, Belgium; and { University of Pennsylvania, Philadelphia, PA Purpose: This study investigates the enhanced conformality of neutron dose distributions obtainable through the application of intensity modulated neutron radiotherapy (IMNRT) to the treatment of prostate adenocarcinoma. Methods and Materials: An in-house algorithm was used to optimize individual segments for IMNRT generated using an organ-at-risk (OAR) avoidance approach. A number of beam orientation schemes were investigated in an attempt to approach an optimum solution. The IMNRT plans were created retrospectively for 5 patients previously treated for prostate adenocarcinoma using fast neutron therapy (FNT), and a comparison of these plans is presented. Dose distributions and dose–volume histograms (DVHs) were analyzed and plans were evaluated based on percentage volumes of rectum and bladder receiving 95%, 80%, and 50% (V95, V80, V50) of the prescription dose, and on V60 for both the femoral heads and GMmuscle group. Results: Plans were normalized such that the IMNRT DVHs for prostate and seminal vesicles were nearly identical to those for conventional FNT plans. Use of IMNRT provided reductions in rectum V95 and V80 of 10% (2–27%) and 13% (5–28%), respectively, and reductions in bladder V95 and V80 of 12% (3–26%) and 4% (7–10%), respectively. The average decrease in V60 for the femoral heads was 4.5% (1–18%), with no significant change in V60 for the GMmuscle group. Conclusions: This study provides the first analysis of the application of intensity modulation to neutron radiotherapy. The IMNRT technique provides a substantial reduction in normal tissue dose in the treatment of prostate cancer. This reduction should result in a significant clinical advantage for this and other treatment sites. Ó 2007 Elsevier Inc. Intensity-modulated neutron radiotherapy, Fast neutron radiotherapy, Prostate radiotherapy, Optimization.

normal tissue doses resulting from the application of intensity modulation to fast neutron radiotherapy is investigated here. Several groups have shown that a combination of photons and neutrons have a therapeutic advantage when compared with photons alone in the treatment of adenocarcinoma of the prostate (1–6). Forman et al. (7) conducted Phase II and III trials to determine the optimum combination of neutron and photon dose and their order of delivery, respectively. For locally advanced prostate cancer, a dose of 10 Gy from neutrons + 38 Gy from photons resulted in fewer complications and higher therapeutic ratio versus 15 Gy from neutrons + 18 Gy from photons. A detailed description of this treatment technique has been discussed previously (8, 9). Currently, a combination of 10 Gy in 10 fractions of neutron

INTRODUCTION The rationale for fast neutron radiotherapy in the treatment of certain types of late-stage prostate and head and neck cancers is based on its radiobiologic advantages. Neutrons interact to produce high LET secondary particles which result in cell killing primarily because of direct interaction with the DNA in the cells. The higher ionization density of resulting charged particle tracks creates complex damage that is more difficult to repair than that caused by low LET radiation. Neutron therapy is thus much less sensitive to the repair capacity and oxygen status of tumor cells. This enhanced effectiveness could also translate into increased late normal tissue toxicity. Decreasing neutron absorbed doses to normal tissues is, thus, of paramount importance. The potential reduction in

Conflict of interest: none. Received Jan 11, 2007, and in revised form April 11, 2007. Accepted for publication April 12, 2007.

Reprint requests to: Lakshmi Santanam Ph.D., Department of Radiation Oncology, Washington University School of Medicine, Campus Box 8224, 4921 Parkview Place, St. Louis, MO 631101093. Tel: (314) 747-3721; Fax: (314) 747-9557; E-mail: [email protected] 1546

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therapy followed by 45 Gy of photon therapy is being used at the Karmanos Cancer Institute fast neutron radiotherapy facility. Earlier studies of conventional photon radiotherapy for prostate cancer (10, 11) have shown that six-field techniques involving two lateral and four oblique fields have resulted in greater normal tissue sparing. Our conventional mixed beam technique includes gantry angles of 45, 135, 225, 90, 270, and 315 degrees, similar to the beams suggested by Xiao et al. (12). It should be noted that the current study does not compare the combined photon and neutron dose distributions. This study exclusively deals with the neutron portion of the dose, as the photon component has already been optimized using intensity modulation. One needs to combine the RBE weighted dose distribution for the neutron component with photon dose distributions to understand the combined effects of the two modalities. This becomes more complicated because of the need for radiobiologic treatment planning parameters. This study is aimed at establishing the superior physical dose distributions obtainable using intensity modulated neutron radiotherapy (IMNRT) when compared with the current six-field conformal neutron therapy technique. As a first step in the investigation of intensity modulated neutron radiotherapy, we have chosen to investigate the application of inverse-planned, aperture-based techniques. The choice of segments for this technique is based on results from previous studies using forward planning intensity modulated radiotherapy (IMRT) techniques for the treatment of prostate cancer using photons (12–18). These groups suggested that using smaller segments that avoid the critical structures and optimizing their weights would yield superior dose distributions when compared with three dimensional (3D) conformal therapy. These forward planning techniques were used as an initial step towards the more complicated beamlet-based inverse planned IMNRT. Studies involving dose complications for the rectum and bladder exist for neutrons as well as photons (19–22, 38). Normal tissue complications in neutron therapy appear to be related to the total dose and not the treatment volume (21, 22, 38). Photon therapy studies by Benk et al. (23) and Bedford et al. (10) have suggested recording percentage volumes corresponding to 90% and 80% dose, which corresponded to the portions of the rectum receiving close to the target dose. They also recorded the percent volume corresponding to 50% dose, which corresponded to the fraction of the rectum receiving moderate to high dose for comparing rival plans. Note that they recorded two percent dose levels, namely 90% and 80%, for two dose prescriptions of 64 and 74 Gy, which were based on the TD(5/5) for rectum. They also suggested recording the percent volume greater than or equal to 70% dose for the femoral heads, which corresponded to 52 Gy (the TD(50/5) for femoral heads based on Emami et al. (19)). Recording percentage volumes receiving 95%, 80%, and 50% dose (referred to as V95, V80, V50), for the critical structures like the rectum and bladder, along with the percentage volume receiving 60% dose (V60) for the femoral heads similar to the suggested photon dose constraints could establish clear ranking criteria to compare rival plans in neutron therapy.

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Studies by Chuba et al. (24) suggested a dose–volume relationship for hip toxicity in radiotherapy patients. Though numerical dose–volume parameters for femoral heads and hip-muscles were not reported, they suggested that higher neutron dose to higher volume led to an increased incidence of hip toxicity and recommended sparing the femoral heads and the hip muscle groups, especially the gluteus muscle (GM) group (gluteus medius, gluteus minimus, and tensor fascia lata). They also suggested that when the total prescribed neutron dose was kept to <13 Gy, fewer hip stiffness complications were observed. During the optimization process, we ensured that the hip muscle groups received either a similar or lower dose in comparison to the conventional plan. This study aims to assess the potential improvement in physical dose distributions available through the application of intensity modulation to the treatment of adenocarcinoma of the prostate with fast neutrons. Five patients previously treated at our center with conventional 3D conformal fast neutron radiotherapy for prostate cancer were retrospectively replanned using forward planned segments. These segments were chosen based on organ at risk (OAR) avoidance and an inverse planning optimization algorithm was used to optimize the weights of each segment based on physical dose characteristics specified as constraints on the dose–volume histograms (DVHs). Several optimized plans were created for each patient and these were compared with 3D conformal treatment plans created for patient treatment. METHODS AND MATERIALS Treatment planning An in-house treatment planning system VRSplan (25) was used to generate both the conventional 3D conformal and IMNRT treatment plans. The treatment planning process for prostate IMNRT involves outlining the following structures: bladder, rectum, pelvic lymph nodes, femoral heads, urethera, skin, three hip-muscle groups including the GM group described above, the adductor muscle (AM) group (adductor magnus, adductor longus, adductor brevis), and the iliopsoas muscle group (IPM) (iliopsoas associated), in addition to the gross tumor volume (GTV) of prostate and seminal vesicles (GTVPros and GTVSV) on the CT image of the patient. The GTV is defined as the ‘‘gross palpable or visible/demonstrable extent and location of malignant growth’’; the clinical target volume (CTV) includes the GTV ‘‘and/or sub-clinical microscopic malignant disease which have to be eliminated.’’ The planning target volume (PTV) is defined as the CTV with an appropriate margin to include organ motion and setup uncertainties based on the ICRU 50 and ICRU 62 reports (26, 27). In this study, the GTV and the CTV are equivalent. The PTV corresponds to the GTVPros and GTVSV with an additional 1.0-cm margin. The rectum and bladder were modified such that any voxels that overlapped with the target were assigned to the target, as the optimizer must assign only one identity to each individual voxel. Thus, the nonoverlapped portion of the rectum and bladder were used for optimization purposes. However, the whole rectum and bladder were used when evaluating the DVH parameters. The GTVpros, PTV, rectum, bladder, the GMmuscle group, and the IPMmuscle group are shown in Figure 1. The overlapped region of the critical structures needs to be treated to the target dose, whereas the nonoverlapped portion needs to be spared. It was ensured that the hot spot was inside the target and not in the critical structures.

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gaussian, cauchy, and tuning, along with one stochastic gradient strategy and one deterministic gradient strategy were used. Because each strategy adopted a unique method to reach the minimum of the objective function, the probability of the optimum solution getting trapped in local minima was eliminated. A detailed description of these strategies as applied to the optimization algorithm can be found elsewhere (33). The objective function is based on three-point DVH constraints. The three points (A, B, and C) correspond to the maximum dose, minimum dose, and the goal dose to the minimum percent volume of the target. For the OARs, the maximum dose and minimum dose along with the limit dose to the maximum percent volume is specified. The objective function OFPTV is defined as follows:

Fig. 1. A computed tomographic slice from Patient 1 showing the gross tumor volume of the prostate (GTVpros) and planning target volume (PTV) (green), Rectum not overlapping with the PTV (cream), Bladder not overlapping with the PTV (input for optimization purposes) (yellow), gluteus muscle (GMmuscle) group (white) and IPMmuscle group (black) are shown. For conventional 3D conformal fast neutron therapy in our center, the field defining apertures for the PTV are based on a margin of 1.5 cm in the superior and lateral direction and 2.0 cm in the anterior and inferior direction along with a 0.5- to 0.75-cm margin in the posterior direction around the GTV; this GTV includes both GTVPros and GTVSV. A six-field arrangement is used in which the fields are optimized manually for adequate coverage of the PTV. The dose is prescribed to the highest isodose curve encompassing the PTV. For fair comparison, the IMNRT plans were compared with conventional plans with a 1.2-cm margin for the beam aperture. Using a smaller margin for the beam aperture for the conventional plan results in inadequate target coverage. This 1.2-cm margin was chosen as being clinically acceptable for patient setup uncertainty and immobilization. Note that plans with the 1.5-cm margin, which were used for actual patient treatment, are also included. The VRSplan treatment planning system uses a differential scatter air ratio (DSAR) algorithm to calculate the dose distribution and earlier studies have shown the accuracy of the DSAR algorithm for conventional 3D conformal fast neutron radiotherapy and IMNRT (28, 29).

Fast neutron therapy facility Fast neutrons used for neutron radiotherapy at the Karmanos Cancer Institute are produced by the d(48.5)+Be reaction using deuterons accelerated in a superconducting cyclotron. The depth dose characteristics are similar to a 4-MV photon beam and the neutron beam exhibits a depth of maximum dose of 9 mm. A detailed description of the cyclotron is given by Maughan et al. (30). A multi-rod collimator (MRC) (31) is used for shaping the required irregular fields. Recently, a multileaf collimator (MLC) with 120 tapered leaves projecting a 0.5-cm width at the isocenter has been installed and commissioned (32, 36). The present study, however, was performed before the completion of the new MLC. The installation of the MLC will make the shaping of these fields easier and could be used for more sophisticated beamlet-based IMNRT in the future.

Optimization of IMNRT A parallel platform based optimization algorithm utilizing six different schemes developed in-house for the VRSplan treatment planning system by He et al. (33) was used for optimization of segment weights. Four evolutionary search strategies, namely discrete,

OFPTV ¼ WA zðDA  DA; P Þ þ WB zðDB; P  DB Þ þ Wc zðDC; P  Dc Þ þ WL LPTV ;

(1)

where W and D corresponds to the weighting factors and doses for points A, B, and C respectively. Note that these weighting factors are the penalty factors corresponding to the maximum, minimum, and goal penalty and are specified by the users. Increasing the goal/limit penalty increases the cost for that structure. Thus, the optimization algorithm will try harder to maintain the goal/limit dose for the structure which has the greatest penalty. P corresponds to the Prescription Dose and L corresponds to the least mean square deviation term. The function z(x) is defined as

2ðxÞ ¼ 0 ðif x#0Þ; ¼ x ðif x.0Þ

(2)

LPTV is expressed as

LPTV ¼

1

X

ðDC; P ÞPTV

1#i#m

ðdi  DC; P Þ

2

(3)

where di is the dose at the i-th sample point in PTV and m is the total number of sample points. DC,P, is the goal dose prescribed to the PTV. Similar equations were specified for the OARs. The total objective function (OF) is the weighted sum of the objective functions of the individual PTVs and OARs, and is expressed as

OF ¼

1

X

ðDC; P ÞPTV 1#i#k

Wi OFi

(4)

where Wi and OFi are respectively, the weighting factors and the objective functions of the i-th PTV or OAR structures. These weighting factors can be manipulated by the user to vary the importance of each structure for achieving a specific goal. Although the input parameters such as the minimum, maximum, and goal/limit dose were based on the prescription suggested by the physician, the penalties and the weights are based on intuitive variation. Table 1 shows the input parameters for the DVH constraints. For all plans, the following penalties and weights were used as a starting point. The goal penalty of 5 was used for the GTVPros, GTVSV, and PTV, a limit penalty of 3 was used for the rectum and bladder, and the weight for all these structures was 4. This starting point was obtained after numerous manual iterations of the penalties and weights for a single patient, thus leading to an easier start point for the other four patients. For each patient, further iterations of the penalties and weights were attempted. Increasing the penalty for a structure spared the structure at the cost of target coverage. A balance of the increased sparing of the critical structure and adequate coverage of the target yielded the goal parameters that are shown in Table 2. These

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Table 1. Input parameters for the optimization algorithm for a single dose fraction of 180 cGy Structure

Minimum dose (cGy/fx)

Maximum dose (cGy/fx)

Goal/limit dose (cGy/fx)

Percent volume

GTVPSV PTV Rectum Bladder Femoral heads

171 171 120 120 50

189 189 160 160 120

180 180 144 144 120

95 95 20 20 20

Abbreviations: GTVPSV = gross tumor volume of the prostate and seminal vesicles; PTV = planning target volume. Note that although the daily fraction dose for neutrons was 100 cGy, the default parameters of the optimization algorithm reflect a fraction size of 180 cGy; one then needs to scale the dose to the required total dose of 10 Gy. parameters were fairly constant for the 5 patients planned. Patient parameters differ, and the information presented in Table 2 can be used as a starting point. The optimization algorithm yields different solutions based on the input parameters because of the different optimization schemes used. The best score solution is chosen for the final plan evaluation. The optimization algorithm generates solutions continually and automatically saves the best solution thus far. Segments with weights leading to less than 5 MU were considered negligible and discarded, and the optimization was subsequently re-run with those segments removed.

Inverse planning for intensity modulated neutron radiotherapy To determine the optimal beam arrangement for the IMNRT fields, 14 different beam arrangements suggested by different groups for the treatment of adenocarcinoma of the prostate were used as a starting point (10–16). These plans included beam angles and segment margins as suggested by these groups. Note that all these beam orientations and segments were studied for a single patient, and the best techniques were then attempted on the remaining 4 patients. The shapes of the primary fields were defined as the prostate and seminal vesicle CTVs in the beam’s eye view plus a combination of 1.5-cm and 1.2-cm margins. The OAR avoidance segments (for the rectum and the bladder) for all gantry angles were defined as the primary field with 1.2-cm margin minus the individual OAR in the beam’s eye view. Finally, smaller segments encompassing the CTV with a 1-cm margin were also defined and input into the optimization algorithm. Similar beam segmentation techniques have been suggested by other groups for forward planning with photons (12, 14, 15). Note that the different fields have been assigned the following notation. The conventional fields with a 1.5-cm margin are named

based on their orientation, namely RPO, LAO, LPO, RPO, RIGHT, and LEFT; segments with 1.2-cm margin are named RAOCD, LAOCD, RPOCD, LPOCD, RIGHTCD, LEFTCD; segments encompassing the PTV only are named RIGHTCD1 and LEFTCD1; and, segments avoiding the OARs, RAOOAR, LAOOAR, etc. Figure 2 shows the beam’s eye view of the three segments: the left anterior oblique (LAO) which is the primary field with a 1.5-cm margin, LAO field with a 1.2-cm margin (LAOCD), and left anterior oblique avoiding the OAR namely the bladder (LAOOAR). Plans that yielded nonconformal dose distributions or high critical structure doses were automatically discarded. The three techniques that yielded the best conformality were then attempted on the remaining 4 patients. These three optimized plans along with the conventional plans are shown in Table 3. The first plan (IMNRT9) was based on an 18-field plan: six fields with a 1.5-cm margin, six fields with a 1.2-cm margin, and six segments avoiding the OAR (rectum). After discarding segments with very low weights, the optimization algorithm yielded a nine-field plan. The nine segments included the two conventional fields from right anterior oblique (RAO) and left anterior oblique (LAO) with a 1.5-cm margin, along with the six

Table 2. Goal and limit penalty parameters used during optimization Structure

Goal/limit penalty

Weight

GTVpros GTVSV PTV Rectum Bladder Femoral heads GM Normal tissue

8 8 8 5 5 2 2 1

10 10 6 7 4 1 1 2

Abbreviations: GM = gluteus muscle; GTVpros = gross tumor volume of the protate; GTVSV = gross tumor volume of the seminal vesicles; PTV = planning target volume.

Fig. 2. The conventional left anterior oblique (LAO), LAO with 1.2-cm margin (LAOCD) along with a segment avoiding the bladder LAOOAR for the optimized plans. Also seen are the rectum (yellow) and bladder (green), along with gross tumor volume of the prostate (GTVpros) and gross tumor volume of the seminal vesicles (GTVSV) and planning target volume (PTV) (red).

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Table 3. List of plans, gantry angles, and margins generated for plan comparison Plan ID

Plan name

Conventional1 plan Conventional2 plan IMNRT9

Plan with 6 fields Plan with 6 fields Optimized plan with 9 segments includes segments from Conventional2, RAO, LAO, LPOOAR Optimized plan with 11 segments, includes segments from IMNRT9 and RIGHT CD1 and LEFTCD1 Optimized plan with 13 segments, includes segments from IMNRT11 and RAOOAR and LAOOAR

IMNRT11 IMNRT13

Gantry angles

BEV margins on CTV

45,90,135,225,270,315 45,90,135,225,270,315 45,90,135,225,270,315, 315,45,135

1.5 cm 1.2 cm 1.2 cm, 1.5 cm

45,90,135,225,270,315,315,45, 135,90, 270

1.2 cm, 1.5 cm, 1.0 cm

45,90,135,225,270,315,315,45, 135,90,270,315,45

1.2 cm , 1.5 cm, 1.0 cm

Abbreviations: CTV = clinical target volume; GM = gluteus muscle; IMNRT = intensity modulated neutron radiotherapy; LAO = left anterior oblique; LPO = left posterior oblique; OAR = organ at risk; RAO = right anterior oblique. Normalization of plans was based on the following criteria: 95% of the GTV is covered by the prescribed dose, and 95% of the PTV is covered by 90% of the prescribed dose. For comparing rival plans, the DVHs for different treatment plans were obtained. The V95, V80, and V50 for the bladder and the rectum for five different treatment plans were compared. Similarly, V60 was determined for the femoral heads and the different muscle groups. These parameters are discussed in detail along with the DVHs for a single patient. The optimum plans were also evaluated by observing whether the 50% isodose line was less than the full rectum width and the proximity of the 80% isodose line to the prescription isodose line. This presented a qualitative way to ensure rapid dose gradient across the rectum.

fields for conventional plan with a 1.2-cm margin, and a segment from left posterior oblique avoiding the rectum (LPOOAR). The second plan (IMNRT11) is an 11-segment plan using the same fields as the nine-field plan with two additional lateral segments encompassing the PTV only. These lateral segments, named RIGHT CD1 and LEFTCD1, avoided the bladder and the rectum from the anterior and posterior directions, respectively. The third plan (IMNRT13) has 13 segments and uses the segments and angles from the 11-field plan with two additional segments, right anterior oblique (RAOOAR) avoiding the bladder and left anterior oblique (LAOOAR), avoiding the bladder. The optimization resulted in relatively low weighting for the RPOOAR segment, and this segment was thus discarded from all three optimum plans for all 5 patients. These plans were compared with the conventional plan with 1.5-cm beam aperture margin around the CTV, which is currently being used for treatment. Finally, a plan with similar gantry angles as the conventional plan but with a 1.2-cm margin was also generated and compared.

RESULTS Plan evaluation The DVHs for the GTVProstate, rectum, bladder, the GM muscle group, and the femoral heads for five different treatment plans are shown in Figures 3 to 7 for a single patient. These plans are those presented in Table 3, namely, the six-field plan (Conventional1 plan), six-field plan with

Plan evaluation Isodose distributions along with DVHs for the critical structures and GTVPros, GTVSV, and PTV were used for plan evaluation.

DVH (GTVProstate) 100 90

Percent Volume

80

Conventional1 plan

70

Conventional2 plan

60

IMNRT9 plan IMNRT11 plan

50

IMNRT13 plan 40 30 20 10 0 0

20

40

60

80

100

120

Dose (cGy)

Fig. 3. Dose–volume histogram for the gross tumor volume of the prostate (GTVprostate) for five plans for Patient 1.

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DVH (Rectum) 100 Conventional1 plan

90

Percent Volume

Conventional2 plan 80

IMNRT9 plan

70

IMNRT11 plan IMNRT13 plan

60 50 40 30 20 10 0 0

20

40

60

80

100

120

Dose (cGy)

Fig. 4. Dose–volume histogram for the rectum for five plans for Patient 1.

1.2-cm margin (Conventional2), nine-segment plan (IMNRT9), 11-segment plan (IMNRT11), and 13-segment plan (IMNRT13) described earlier. The optimized DVHs for GTVProstate are nearly identical to those of the conventional plans. The average hotspot for the nine, 11, and 13 segment plans is 104%, 105%, and 107%, respectively, compared with 103% for conventional plans. As for the GTVSV, the mean dose was 103% for conventional plans, and 102% for the optimized plans. The PTV coverage was uniform with the cold spot, varying from 71% to 81% for all the plans. On average, the IMNRT plans yielded a higher PTVmin than the corresponding Conventional1 plans. Finally, it was ensured that no more than 5% of the PTV received less than 90% dose for both conventional and IMNRT plans.

It can be seen from the DVHs of the critical structures that the optimized IMNRT11 and IMNRT13 plans are superior to the Conventional2 with 1.2-cm margin and the Conventional1 plan. The Conventional1 is the one which is currently used for fast neutron therapy at Karmanos Cancer Institute. Table 4 shows percent volumes corresponding to 95%, 80%, and 50% doses for the bladder, rectum, femoral heads, and the GMmuscle group. Table 5 shows these parameters for the other 4 patients planned. Figures 8 and 9 show the isodose distributions for the Conventional1 plan and IMNRT13 plan for Patient 2 in Table 5. The conformality of high dose isodose lines, specifically the 80% line, is clearly visible in the IMNRT13 plan, thus providing better rectal sparing. The Conventional1 and

DVH (Bladder) 100 Conventional1 plan

Percent Volume

90

Conventional2 plan

80

IMNRT9 plan

70

IMNRT11 plan IMNRT13 plan

60 50 40 30 20 10 0

0

20

40

60

80

100

Dose (cGy)

Fig. 5. Dose–volume histogram for the bladder for five plans for Patient 1.

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DVH (GMmuscle group) 100 Conventional1 plan

90

Conventional2 plan IMNRT9 plan

80

IMNRT11 plan

Percent Volume

70

IMNRT13 plan

60 50 40 30 20 10 0 0

20

40

60

80

100

120

Dose (cGy)

Fig. 6. Dose–volume histogram for the gluteus muscle (GM) group for the five plans for Patient 1.

Conventional2 plans yielded a dose distribution with the 50% isodose line encompassing a large amount of normal tissue. The optimized plans reduced this large 50% dose coverage. The V50 for total normal tissue was determined from the DVHs and it was seen to vary from 12% for the conventional plan to 8% for all three optimized plans. The DVH for the rectum shows a definite reduction for the IMNRT13 plan as discussed below. The V95 for the rectum decreases from 22% for the Conventional2 plan to 4% for the IMNRT13 plan. The V80 decreased from 48% for the Conventional2 plan to 20% for the IMNRT13 plan. Such a significant reduction in the volume of the rectum receiving high doses should improve the outcome of the treatment with IMNRT. The small increase in maximum dose within the target was considered to be clinically insignificant.

The V95 and V80 for the bladder decreases from 15% to 5% and from 21% to 12%, respectively, from the Conventional2 plan to the IMNRT13 plan. Small variations are seen for the bladder DVHs at the high dose regions as can be seen in Fig. 5. It was ensured that the femoral heads did not get significantly higher doses when compared with the conventional plan. Similar constraints were applied to the GMmuscle. Although the V60 was similar to the conventional plan with 1.2-cm margin, it was seen on comparing the DVH’s that the V40 decreased by 10% for both the optimized plans. The values of the ranking parameters for the other 4 patients are shown in Table 5. The first patient in Table 5 was an interesting case. Sparing of the bladder and rectum was a prime criterion because of prior treatment. The use of the 13 segments reduced the

DVH (Femoral heads) 100 Conventional1 plan

90

Percent Volume

Conventional2 plan 80

IMNRT9 plan

70

IMNRT11 plan IMNRT13 plan

60 50 40 30 20 10 0 0

20

40

60

80

100

Dose (cGy)

Fig. 7. Dose–volume histogram for the femoral heads for five plans for Patient 1.

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Table 4. Percentage volumes corresponding to different doses for the critical structures of a sample patient for five plans Structure

Conventional1 plan

Conventional2 plan

IMNRT9

IMNRT11

IMNRT13

Rectum V95 Rectum V80 Rectum V50 Bladder V95 Bladder V80 Bladder V50 Femoral heads V60 GM V60

22 48 78 15 21 43 6 30

12 48 78 15 19 43 7 12

19 38 77 13 18 43 10 18

8 18 78 11 18 50 5 10

4 20 72 5 12 45 5 12

Abbreviations: GM = gluteus muscle; IMNRT = intensity modulated neutron radiotherapy.

V95 of the rectum from 25% to 10% while the bladder V95 was reduced from 30% to 18%. The dose to the femoral heads increased by 8%, whereas the dose to the GMMuscle group increased by 10%. An increase of 8% to 10% in this case might not be clinically significant, as the total neutron dose to the hip muscles and femoral heads is still only 5 Gy. On the other hand, reduction of the high dose–volume coverage for the rectum and bladder is significant in this situation. For all

5 patients who underwent planning, the V95,V80, and V50 for the rectum and bladder indicated the IMNRT13 plan as the optimum solution. This is true even when, in certain situations the V95 and V80 for the bladder and rectum were similar for the IMNRT11 and IMNRT13 plans. In such situations, the IMNRT13 plan yielded better conformality of high-dose isodose around the PTV along with better sparing of the femoral heads and GMMuscle group. Although the plans presented

Table 5. Percentage volumes corresponding to different doses for the critical structures of 4 other patients planned retrospectively Structure Patient 2 Rectum V95 Rectum V80 Rectum V50 Bladder V95 Bladder V80 Bladder V50 Femoral heads V60 GM V60 Patient 3 Rectum V95 Rectum V80 Rectum V50 Bladder V95 Bladder V80 Bladder V50 Femoral heads V60 GM V60 Patient 4 Rectum V95 Rectum V80 Rectum V50 Bladder V95 Bladder V80 Bladder V50 Femoral heads V60 GM V60 Patient 5 Rectum V95 Rectum V80 Rectum V50 Bladder V95 Bladder V80 Bladder V50 Femoral heads V60 GM V60

Conventional1 plan

Conventional2 plan

IMNRT9

IMNRT11

IMNRT13

25 43 79 30 60 88 42 40

12 35 75 22 45 64 45 30

11 29 65 20 40 70 85 64

12 32 69 18 40 79 50 35

10 30 65 18 38 69 50 50

12 28 75 32 50 69 80 54

12 32 75 20 35 68 69 48

18 42 75 22 38 65 70 0

5 21 70 15 33 60 87 28

7 20 70 10 25 65 68 38

20 60 82 20 31 47 38 9

13 62 75 41 22 35 30 8

8 50 75 19 27 42 62 5

12 30 75 13 22 40 60 8

5 42 77 15 25 45 25 0

17 52 73 26 30 69 18 42

38 54 73 15 25 68 30 12

25 40 70 15 25 65 45 33

12 32 65 2 25 60 20 29

11 33 70 12 26 65 12 12

Abbreviations: GM = gluteus muscle; IMNRT = intensity modulated neutron radiotherapy.

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Fig. 8. Isodose display of the Conventional2 plan using six fields with manual optimization.

here may only be optimal for particular patients, one could incorporate all OAR-avoidance segments presented in this study and allow the optimization algorithm to yield a more patient-specific solution on a case-by-case basis. This study demonstrated that three relatively simple IMNRT solutions yielded substantial reduction in normal tissue dose. DISCUSSION These results suggest that there is a definitive improvement from the conventional plan and further dose escalation is possible. Previous studies have established 10 Gy to be the optimum neutron dose with respect to GI/GU complications (7). Studies involving dose escalation using photon IMRT up to 86.4 Gy in the treatment of prostate cancer have been established (34). Currently, the mixed photon/neutron regimen leads to a dose equivalent of 85 Gy. Because of the high dose conformality and better normal tissue sparing, it may be possible to increase the neutron component. This provides a benefit for the treatment of prostate cancer since there is a significant relative biologic effectiveness (RBE) advantage. Clinical RBE values of approximately 4 have been observed for prostate tumors, however, RBE

values of only approximately 3 have been observed for rectum and bladder (37). A feasibility study has been previously presented, investigating potential issues such as total body dose and potential changes in neutron RBE (35). None of these issues appear to present a serious impediment to the implementation of IMNRT. The most complex of the IMNRT plans presented here took an average of 50 min for setup and treatment. This can be compared with approximately 30 min for setup and treatment for the conventional plan using the Multirod Collimation system. With the installation of the new MLC, treatment times have been reduced significantly, because the need for manual placement of individual shaped blocks for each field has been eliminated. Current estimates of the total delivery time are 20 min and 30 min for the conventional and IMNRT plans, respectively. We are currently in the process of establishing the feasibility of neutron only IMNRT with tighter margins using image guidance with marker seeds. CONCLUSIONS The optimization algorithm yielded excellent results in conforming to the goal parameters. The average decrease in

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Fig. 9. Isodose display of the intensity modulated neutron radiotherapy plan using 13 segments (IMNRT13) with computer optimization.

V95 and V80 for the rectum, from the conventional to the optimum IMNRT plan was 10% (2–27%) and 13% (5–28%) respectively. The average decrease in V95 and V80 for bladder ranged from 12% (3–26%) and 4% (7–10%), respectively. Earlier studies have shown GI/GU complications have a definite dose–volume relationship and a decrease in the high dose–volumes of the critical structures should be expected to decrease normal tissue toxicity. The decrease in V60 for the femoral heads ranged from 1% to 18%. These results suggest a definitive improvement in reducing the normal tissue doses when compared with con-

ventional fast neutron therapy, and, hence, further dose escalation is possible. Image guidance applied to neutron IMRT will further help in reducing margins and, hence, pave the way for image guided neutron radiotherapy (IGNRT), which will bring the technology for delivery of fast neutron therapy back to the level of the current stateof-the-art in photon radiotherapy. This technologic improvement combined with the biologic advantages inherent in fast neutron therapy will make it an optimal radiotherapy treatment for adenocarcinoma of the prostate, and potentially other sites as well.

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