EVALUATION OF THERAPEUTIC POTENTIAL OF HEAVY ION THERAPY FOR PATIENTS WITH LOCALLY ADVANCED PROSTATE CANCER

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1 doi: /s (03) Int. J. Radiation Oncology Biol. Phys., Vol. 58, No. 1, pp , 2004 Copyright 2004 Elsevier Inc. Printed in the USA. All rights reserved /04/$ see front matter CLINICAL INVESTIGATION Prostate EVALUATION OF THERAPEUTIC POTENTIAL OF HEAVY ION THERAPY FOR PATIENTS WITH LOCALLY ADVANCED PROSTATE CANCER ANNA NIKOGHOSYAN,* DANIELA SCHULZ-ERTNER, M.D., BERND DIDINGER, M.S.C.,* OLIVER JÄKEL, PH.D.,* IVAN ZUNA, PH.D.,* ANGELIKA HÖSS, M.S.C., MICHAEL WANNENMACHER, M.D., D.D.S., AND JÜRGEN DEBUS, M.D., PH.D.* Divisions of *Radiation Oncology and Medical Physics, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany Purpose: To investigate the feasibility of raster scanned heavy charged particle therapy in the treatment of prostate cancer (PCa,) with special regard to the influence of internal organ motion on the dose distribution. Methods and Materials: The CT data of 8 patients with PCa who underwent three-dimensional conformal radiotherapy (RT) were chosen. In addition to the routine treatment planning scan, three to five additional positioning control CT scans were performed. The organs at risk and the target volumes were defined on all CT scans. Primary and boost carbon ion plans were calculated to deliver 66 Gy to the clinical target volume/planning target volume, with an additional 10 Gy to the gross tumor volume (GTV). To estimate the influence of internal organ motion on plan quality, the dose was recalculated on the basis of the control CT scans. The comparative analysis was based on the dose volume histogram derived physical parameters. Results: The average 90% target coverage was 99.1% for the GTV. The maximal dose to the rectum was 71.8 Gy. The average rectal mean dose was 19 Gy. The volume of the rectum receiving 70 and 68 Gy was 0.1 and 0.3 cm 3. The average difference in the 90% coverage for the GTV on control CT cubes was 3.6%. The maximal rectal dose increased to 76.2 Gy. The deviation in the mean rectal dose was <1 Gy on average. The rectal volume receiving 70 and 68 Gy increased to 2.5 and 3.3 cm 3. Conclusion: The investigation demonstrated the feasibility of raster scanned carbon ions for PCa RT. Excellent coverage of the target volume and optimal sparing of the rectum were acquired. The combination of photon intensity-modulated RT and a carbon ion boost to the GTV is the most rational solution for the gain of clinical experience in heavy ion RT for PCa patients Elsevier Inc. Prostate cancer, Carbon ion therapy, Internal organ motion. INTRODUCTION Heavy charged particle radiotherapy (RT) has been under clinical investigation as the number of proton and heavy ion facilities has risen worldwide (1). Since 1997, the carbon ion medical facility in Gesellschaft für Schwerionenforschung (Darmstadt, Germany) has been in use for patient treatment. More than 130 patients have already been treated in a pilot project. On the basis of the promising clinical results obtained by carbon ion RT for chordomas and chondrosarcomas of the skull base recently published by Schulz- Ertner et al. (2), a dedicated ion therapy facility in Heidelberg has been proposed (3). The planned hospital-based heavy ion facility will provide the capacity to treat 1000 patients annually and, therefore, allow a broadening of the spectrum of indications for ion therapy to include more common tumors such as prostate cancer (PCa) and softtissue sarcomas. Reprint requests to: Anna Nikoghosyan, Division of Radiation Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg D Germany. Tel: The biologic and physical advantages (inverse dose profile, Bragg peak) of heavy ions can be exploited for the treatment of relatively radioresistant, slowly proliferating, and late responding tumors. PCa is a typical example of such tumors (4 7). Several studies have shown that the radiobiologic effect associated with the use of neutron beams has improved local control of PCa (1, 8). A similar result might be expected with carbon ions, but because of the improved dose distribution, the probability of normal tissue complications will be minimized. Several studies have shown that patients with unfavorable locally advanced PCa might profit from dose escalation to doses 72 Gy (9 14). Dose-limiting structures such as the rectum, adjacent to the prostate preclude the safe delivery of such high doses using conventional RT. Modern high-precision treatment modalities, such as stereotactically guided intensity-modulated RT (IMRT), as well as proton and ; Fax: ; a.nikoghosyan@dkfz.de Received Oct 25, 2002, and in revised form May 8, Accepted for publication Jun 26,

2 90 I. J. Radiation Oncology Biology Physics Volume 58, Number 1, 2004 heavy ion therapy, are able to confine the high-dose distribution to the target. Because of the steep dose fall-off, high-precision RT is more sensitive to organ motion and positioning errors. In the case of PCa, numerous investigations of internal organ motion (tumor, rectal volume) have been performed (15 20). Moreover, charged particle RT is more sensitive to organ motion than photon RT. There are several indications that high linear energy transfer RT may result in an advantage in the treatment of PCa patients. This study investigates the potential and feasibility of carbon ion therapy in the RT for PCa with special regard to the influence of internal organ motion and rectum filling variation on the dose distribution during the course of RT. METHODS AND MATERIALS Patient characteristics and definition of volumes of interest For this study, 8 patients with PCa who originally received photon IMRT using a 15-MV linear accelerator (Primus, Siemens) at Deutsches Krebsforschungszentrum, DKFZ, German Cancer Research Center were chosen. Two of the patients had Stage T1, 4 had T2, and 2 had T3. The initial prostate-specific antigen levels varied from 5 to 26.8 ng/ml. Patient characteristics (gross tumor volume [GTV] and volume of rectum and bladder) are presented in Fig. 1. Patients were treated in the supine position. A custommade, individually manufactured, body mask system (Scotch-Cast, 3M) was used for noninvasive patient fixation and ensured the accuracy of the patient alignment to within 3.6 mm in all directions (21) (Fig. 2). CT data were acquired with a 3-mm slice thickness. In addition to the routine treatment planning scan, three to five additional CT scans were performed to control patient positioning during the treatment course. For all patients, the organs at risk such as the rectum, bladder, femur heads, and target volumes were defined according to a protocol. The GTV included the prostate. The clinical target volume (CTV) encompassed the GTV plus a 5-mm margin in all directions, except at the interface with the rectum and bladder, where the margin was the anterior rectal wall and the base of bladder. The CTV included the regions considered to be at risk of microscopic disease plus the seminal vesicles. The planning target volume (PTV) included the CTV with a 5-mm safety margin for variations in treatment setup and organ movement during the treatment course. The rectum was defined from 6 mm in the caudal direction to 6 mm in the cranial direction from the target area (standardized definition for all patients). The bladder was defined as the whole volume, including the cavity. The femur heads were defined to the level of the femoral neck. The average volumes of the GTV for the 8 patients in the planning CT cubes was cm 3. The average volume of the rectum and bladder was and cm 3, respectively. The positioning control CT scans were reconstructed with a 3-mm slice thickness and stereotactically matched with the planning CT cube. The definition of all volumes of interest was performed on the control CT cubes as well. All segmentations were made by the same investigator and under the same conditions. Carbon ion plans The original CT cubes and control CT cubes were used for heavy ion treatment planning. The plans were created with the Voxelplan treatment planning system developed at Deutsches Krebsforschungszentrum, DKFZ, in Heidelberg (22). For each patient, two carbon ion plans (primary plan, optimized for the PTV, and boost plan, optimized for the GTV) were evaluated. The resulting plans were calculated to deliver 66 Gy to the CTV/PTV and an additional 10 Gy to the GTV. The dose calculation and other ion-specific components were performed using the TRiP (TReatment planning for Particles) software package developed at Gesellschaft für Schwerionenforschung in Darmstadt (23). Two opposing lateral fields of scanned ion beams resulted in the optimal dose distribution. The dose distributions from two carbon ion plans were added on a voxel-by-voxel basis in a 66:10 ratio. To assess plan quality, the composite plans were analyzed. It was desired that the GTV and CTV would be covered by the 90% isodose of the prescribed dose. No more than 1 cm 3 of the rectal volume was allowed to receive 68 Gy. No additional attempts were performed to spare the bladder. To estimate the influence of internal organ motion on the carbon ion plan quality, the dose was calculated using the positioning control CT scans. We used the beam data, which were optimized for the CT obtained for treatment planning, and recalculated the dose distribution and dose volume histograms (DVHs) on the control CT. Analysis of dosimetric parameters The comparative analysis used the physical parameters, derived from the DVHs. The following metrics were used for the plan quality estimation: 1. Target conformality index: ratio of the total volume covered by the 90% isodose divided by the volume of the CTV covered by the 90% isodose (59.4 Gy, 90% of prescribed dose of 66 Gy for the CTV) 2. Target heterogeneity: ratio of the clinically relevant maximal dose for the GTV divided by the desired dose to the GTV (76 Gy) 3. Target coverage related to the GTV volume receiving 72 Gy (95% of prescribed dose), 90% target dose coverage for the GTV 4. 95% target dose coverage for the CTV, target coverage related to the CTV volume receiving 60 Gy (90% of prescribed dose) 5. Clinically relevant minimal dose for the GTV and CTV

3 Therapeutic potential of heavy ion therapy for locally advanced PCa A. NIKOGHOSYAN et al. 91 Fig. 1. Volumes of (a) GTV, (b) rectum, and (c) bladder in routine treatment planning scan (rtp scans, circles) and positioning control CT scans (vertical lines); average volume of organs in rtp scans (hyphens). GTV gross tumor volume; rtp routine treatment planning.

4 92 I. J. Radiation Oncology Biology Physics Volume 58, Number 1, 2004 Fig. 2. Fixation of patient with sacral chordoma within body mask (torso). 6. Mean dose for the GTV and CTV 7. Absolute maximal dose for the rectum 8. Clinically relevant maximal dose for the rectum (maximal dose that 1 cm 3 of the volume received) 9. Mean dose for the rectum 10. Rectum volume receiving 70, 68, 60, and 45 Gy 11. Mean dose for the bladder 12. Maximal dose for the bladder 13. Mean dose for the femur heads (24) Fig. 4. DVH for dose distribution shown in Fig. 3. 1, GTV; 2, CTV; 3, PTV; 4, rectum; 5, bladder; 6, left femur head; and 7, right femur head. RESULTS Analysis of dose distribution for original composite plans Figures 3 and 4 show the typical DVH and dose distribution for the heavy ion composite plan prescribed to deliver 66 Gy to the PTV and 76 Gy to the GTV. We analyzed the dose to the CTV and GTV. The analysis of the original composite plan DVHs showed that the average 95% and 90% target dose coverage was 98.3% and 99.8% (SD 0.7 and 0.2, respectively) for the GTV. For the CTV, the average 95% and 90% target dose coverage was 99.1% and 99.6% (SD 0.5 and 0.3, respectively). The 95% and 90% target dose coverage for the CTV was obtained related to the prescription dose of 66 Gy for Fig. 3. Example of carbon ion dose distribution, transversal, sagittal and coronal views. GTV covered with 68.4 Gy isodose (90% of prescribed dose, 76 Gy) and CTV with 60.8 Gy isodose (92% of prescribed dose, 66 Gy). CTV clinical target volume.

5 Therapeutic potential of heavy ion therapy for locally advanced PCa A. NIKOGHOSYAN et al. 93 Fig. 5. Average 95% coverage of GTV and CTV, minimal dose to GTV and CTV, and mean and maximal dose to rectum in routine treatment plans (gray columns) and control CT scans (white columns). the CTV. The average target conformality for all patients was 2 (SD 0.1). The target conformality was noticeably 1 because of the definition of the PTV and the optimization procedure of the primary treatment plans. The normal tissue volume covered by the 90% isodose was increased, because the primary plans were optimized for the PTV, but the target conformality index was defined as a ratio of the total volume covered by the 90% isodose divided by the volume of the CTV covered by the 90% isodose (Fig. 3). The average target heterogeneity was 1 (SD 0.001). The average clinically relevant minimal dose for the GTV and CTV was 71.6 Gy (94% of prescribed dose; SD 1.3) and 63.3 Gy (96% of the prescribed dose; SD 5.9), respectively. The average absolute maximal dose for the rectum was 71.8 Gy (SD 1.4). The clinically relevant maximal dose for the rectum was 64.2 Gy (SD 1.9). The average mean rectum dose was 19 Gy (SD 2.5). The rectal volume receiving 70 Gy was 0.1 cm 3 (range 0 0.2). The rectal volume receiving 68 Gy was 0.3 cm 3 (range ). The rectal volume receiving 60 and 45 Gy was 3 cm 3 (range ) and 15.3 cm 3 (range ). The average mean dose to the bladder was 17.7 Gy (range ). The maximal bladder dose was 76.2 Gy (SD 0.4) on average (Fig. 5). The maximal doses to the femur heads were on average not more than 50 Gy. Analysis of organ motion influence on dose distribution with carbon ions Figure 6 shows the variation of dose distribution in the positioning control CT scans in the transversal view. The analysis of the dose distribution on the basis of the data from the control CT cubes showed an average difference of the 95% and 90% coverage for the GTV of 4.9% (SD 3.6) and 2% (SD 1.5), respectively. The average difference of the 95% and 90% coverage for the CTV was 3.6% (SD 3.7) and 2.8% (SD 2.8), respectively. The average difference for the clinically relevant minimal dose was 6.2 Gy for the GTV and 12.5 Gy for the CTV (SD 4.9 and 7.9, respectively). This corresponded to 64.6 Gy and 49.4 Gy on average. The absolute maximal dose for the rectum increased to 76.4 Gy on average (average difference 4.6 Gy, SD 2.5). The clinically relevant maximal dose for the rectum was 70.5 Gy (average difference 6.9 Gy, SD 2.3). The deviation of the mean dose to the rectum was 1 Gy on average. In general, the rectal volume receiving 70, 68, 60, and 45 Gy increased to 2.5, 3.3, 7.5, and 18 cm 3, respectively. The positioning variation had nearly no influence on the mean dose to the bladder. The difference was 0.1 Gy, and the maximal bladder dose increased to 77.5 Gy on average. All presented differences were statistically significant (p ). DISCUSSION The results of the present study demonstrate that carbon ions are feasible for PCa RT. Using only two lateral horizontal scanning beams, we acquired excellent coverage of the target volume and optimal sparing of the rectum. The potential biologic advantage of heavy ions was not taken into account in the present investigation, although the biologic effectiveness might have an impact on outcome. It is a long way from a virtual study to the practical use of a new treatment modality and several questions have to be discussed. Modern RT techniques and adaptive RT (ART), which more tightly confine the high-dose distribution to the target volume, decrease the risk of rectal toxicity. The grade of side effects from RT is dose dependent. We were conservative with the definition of the dose limits for the rectum, allowing 68 Gy only to 1 cm 3 of rectal volume. Even this condition was successfully fulfilled with carbon ion therapy. Other studies made their investigations of complication probability permitting a greater dose to the rectum and found a correlation between Grade 2 complications and the volume of rectum receiving 75 Gy (11, 14, 25). Also, the correlation between the rectal volume in the overlap region and complication probability indicates that the overlap region must be minimized by precise RT methods (14). Kupelian et al. (26) performed a study to deter-

6 94 I. J. Radiation Oncology Biology Physics Volume 58, Number 1, 2004 Fig. 6. Example of carbon ion dose distribution variations due to inner organ movement, transversal view. mine the independent predictors of rectal bleeding and found that only the absolute rectal volume receiving the prescribed dose (in that case 78 Gy for conformal RT and 70 Gy for IMRT) correlated significantly with rectal toxicity. They recommended that no more than 15 cm 3 of the rectal volume should receive the prescribed dose (26). The variation in the rectal volume receiving 70 Gy with heavy ions owing to positioning variations was 3 cm 3. The radiation tolerance of the urinary tract is associated with uncertainties. The tolerance dose of the bladder was estimated by Emami et al. (27) to be 80 Gy to two-thirds of the bladder volume and 65 Gy to the whole bladder. A more recent study estimated the complication rate to be as great as 5 10% at doses of Gy delivered to less than twothirds of the bladder volume (28). Our study showed that with carbon ion therapy, 20 Gy is delivered to 50% of the bladder. It has been demonstrated in a large number of studies that the patients with PCa at risk (prostate-specific antigen level of 10 ng/ml or more, Gleason score 7 or more, and tumor Stage T2b or greater) benefit from dose escalation (9 14, 29). Also, a study of the tumor control probability and normal tissue complication probability for the rectum with partial dose escalation in tumor nodules, using an integrated boost concept, has shown an improved outcome (30). The high precision and sharp dose falloff achieved with carbon ion therapy should allow additional dose-escalation studies to be undertaken. In addition, heavy ions provide biologic advantages, namely the high-linear energy transfer effect. A reduction of the local failure rate was observed in a number of studies of PCa patients treated with high-linear energy transfer fast neutrons and mixed neutron and photon RT (8, 31 33). The results of the Neutron Therapy Collaborative Working

7 Therapeutic potential of heavy ion therapy for locally advanced PCa A. NIKOGHOSYAN et al. 95 Group prospective multicenter study indicated an improvement in the local failure rate using neutrons alone compared with photon RT alone at 5 years (11% vs. 32%, respectively). Similarly, mixed neutron and photon RT improved the failure rate compared with photon RT alone at 10 years (30% vs. 42%, respectively) (31, 33). The rate of severe side effects was very high (36%) using neutrons in that trial, which might be related to the insufficient treatment application technique used. With the progress in the neutron application technique such as higher energies and beamshaping possibilities, the rate of side effects was comparable to the results with photon RT (31). Within a retrospective study in Louvain-la-Nueve (Belgium), mixed photon and neutron RT resulted in a overall survival and progression-free survival rate of 79% and 64% at 5 years, respectively (32). A large Phase II III study involving 700 PCa patients treated with a combination of neutrons and photons was performed at the Wayne State University (Detroit, MI). The optimal dose combination and treatment sequence of neutrons and photons was determined. It was asserted from the study that neutron therapy results in significantly better outcome as determined by disease-free survival compared with photon therapy alone in PCa patients with risk factors (8). Taking into account this favorable result of neutron RT, we have good arguments for the use of heavy ions in patients with locally advanced PCa. Compared with neutron RT, a reduction in the incidence of severe side effects might be expected with the use of carbon ion RT, if active beam delivery is performed. PCa cells react to RT like late responding normal tissue (6, 34). PCa cells have a low / ratio and show high sensitivity toward RT fractionation. Therefore, a larger fraction size and a small number of fractions may provide a better outcome (7) and this should be considered when developing new treatment protocols for carbon ion therapy. Another question is the target coverage. Our study showed that the variation in the 95% isodose coverage was 5% owing to positioning variation; however, we did not have any clinical data and we could not exclude the influence of cold spots in the target areas ( 50 Gy for the CTV) on tumor control probability. It is possible that some means of managing internal organ motion will be required. Precise positioning is a prerequisite for successful RT. Although setup errors can be well reproduced and examined, the main problem is the target movement (prostate motion) due to different volumes of rectum and bladder filling between different treatment sessions. Different studies have shown variations in prostate motion (15, 18 20, 35). Generally, it can be postulated that the prostate motion is larger in the AP and superoinferior directions than in the lateral direction. Rotation is very small (36). We think that all parameters influencing internal organ motion (rectum, bladder filling, leg rotation, setup errors) should be taken into account. The question is how to handle this complex situation. ART theoretically provides an alternative solution because of daily treatment planning and individual evaluation of the target volume. Recently, the ART concept was used in practice and showed improvement in dose delivery and treatment accuracy (37, 38). With the ART techniques, it is possible to evaluate patient-specific treatment planning (clinical target volume and rectum and bladder volume variations). However, ART is not available everywhere and is associated with high costs, complicated computer technologies, and more manpower investment. An alternative can be found in the method of controlled organ filling (rectal balloon, bladder catheter), which is very uncomfortable for the patients, but allows the use of reduced margins, with a corresponding reduction in acute toxicity and dose inhomogeneities due to rectal air (39 41). Therefore, some kind of compromise will be the best possible solution. For instance, performing several CT scans to investigate the individual characteristics of internal organ motion for the creation of patient-specific target volume, giving special instructions to the patients, and controlling the rectum and bladder filling. The biologic effectiveness of carbon ions, the complication probability for the rectum, and feasibility of the new therapy modality requires investigation in adequate experiments, as well as clinically. New dose constrains for organs at risk and probably a new target definition concept must be developed for heavy ion therapy. CONCLUSION To be able to use the potential advantages of heavy charged particles, a new approach to RT for PCa patients has to be designed. The safe dose escalation, excellent target coverage, and decreased rectal toxicity (which can be mentioned only as a theoretical deduction because of the absence of clinical experience and owing to physical characteristics of the particles) are of concern. The combination of protons and photons has already been shown to improve actuarial disease-free survival and tumor control rates as a result of the introduction of particle therapy for PCa (41 43). The combination of photon IMRT and a carbon ion boost to the GTV is the most rational solution to gain clinical experience in heavy ion RT for PCa patients. A clinical Phase III study combining photon IMRT with a carbon ion boost might help to identify the potential biologic advantage of carbon ions clinically. REFERENCES 1. Orecchia R, Zurlo A, Loasses A, et al. 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