Statistical Analysis and Volumetric Dose for Organ at Risk of Prostate Cancer

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1 The African Review of Physics (2013) 8: Statistical Analysis and Volumetric Dose for Organ at Risk of Prostate Cancer F. Assaoui¹,*, A. Bazine² and T. Kebdani³ ¹ Medical Physics Unit, Radiotherapy Department, National Institute of Oncology, Rabat, Morocco ² Radiotherapy Department, Mohamed V Military Hospital, Rabat, Morocco ³ Radiotherapy Department, National Institute of Oncology, Rabat, Morocco The purpose of this work is to evaluate the capability of 3D-CRT by increasing beam's input (10 fields as the reference) (ME.3CRT) and to reduce the volume of organs at risk (OARs), such as bladder, rectum and femoral heads irradiated in men with prostate cancer. Using the treatment planning system XIO version 4.64, two plans, 3D-CRT ''0 fields'' () and a standard ''4 field box'' (4FB.3DCRT) with apertures shaped to the PTV in each beam's eye view, were created for ten men with high risk prostate cancer. The PTV was generated by adding a 7 mm margin of the CTV in all d irections, except posterior position where a 5 mm margin was used. Both plans were normalized to deliver 70 Gy to the PTV. Plans were compared according to dose homogeneity, conformation and dose volume histograms (DVHs), for the volumes of bladder, rectum, femoral heads, prostate (P) and seminal vesicles (SV). The mean PTV conformity index (CI) for 10 fields was 0.74 and 0.81 for a standard 4 field box. The PTV homogeneity index was 0.03 for 10 fields and 0.03 for a standard 4 fields box. The dose distribution in PTV was similar in both the plans. The analysis of DVHs shows a decrease in the mean OARs with 10 fields. Bladder, rectum and femoral head dose was improved by increasing the beam's input (using 10 fields) and with a significant difference in the V60 and V70 for the bladder and rectum, and in the V50, V40 for the femoral heads. Our results suggest that 3D-CRT (10 fields) is an effective means of reducing the volume of organ at risk (bladder, rectum and femoral heads) irradiated in men with prostate cancer. The treatment planning 3D-CRT ''10 fields'' produced dose distribution more favorable than could be achieved with a standard ''4 fields box'' for prostate cancer at the Radiation Therapy Center, which does not have modern 3D-CRT (IMRT, VMAT, ) or ready to use it. 1. Introduction External beam radiation is the treatment of choice for intermediate and high risk prostate cancers, which is considered a low risk option. Radiation doses are more likely to cause significant critical normal tissue morbidity when administered with two-dimensional (2D) radiotherapy approaches. The conformal technique allows a smaller volume of normal tissues to be irradiated with the potential benefit of fewer side-effects and which in turn may allow dose escalation and improved tumor control [1]. There is a consensus that 3D conformal radiotherapy is standard therapy for prostate cancer with doses higher than in pelvic irradiation used before in 2D technique. However, there are differences in the number of fields and beam arrangements at different radiation therapy centers. The goal of this study is to evaluate the capability of 3D-CRT by increasing the Beam's input (10 fields as reference) to reduce the volume of (OARs) organs at risk, such as the bladder, * assaoui2003@yahoo.fr rectum and femoral heads irradiated in men with prostate cancer. 2. Methods and Materials Ten men with high risk prostate cancer were prospectively selected for this study. The median age was 3 years (range: years). The prescribed dose in all patients was 70 Gy but the administered daily dose was 2.0 Gy. For each patient, an initial simulation (Siemens Simulator Scanner 16 barrettes and FOV of 82 cm) was conducted to establish the patient s isocenter as well as the immobilization of the patient. To minimize the setup variability, a custom immobilization device was used in the supine position. Three positional markers were placed in anatomically stable regions, one anterior as reference for the isocenter and two lateral points to assure identical positioning of the patient (laser beams) during computed tomography and irradiation. The scanned parameters consisted of a large field of view pelvic protocol with a 5 mm slice thickness/table index. For our study, the treatment fields for both techniques: 4-Field Box 3D Conformal Radiation Therapy (4FB. 3DCRT)

2 The African Review of Physics (2013) 8: and Multi-Enters 3D Conformal Radiation Therapy 10 fields as reference (ME. 3DCRT) were defined by using the CT for all patients. After the scans have been acquired, they were transferred over the network to the treatment planning system (TPS) and a treatment plan (TP) is generated. TP was performed using the TPS XIO version The doses were calculated using heterogeneity corrections and the beams are weighted so that the prescription isodose line encircles most of the PTV. The target volumes (CTV and PTV) and the organs at risk (rectum, bladder, femoral heads) were outlined on each axial CT slices in the Focal System. The prostate plus seminal vesicles (PSV) and prostate plus seminal vesicles and pelvic lymph nodes (PSVN) contours denoted as the clinical target volumes CTV and CTV1, respectively. The PTV and the PTV1 were generated by adding a 7 mm margin to the CTV and the CTV1 in all directions, respectively, except in the posterior position where a 5 mm margin was used. The treatment was 46 Gy on PTV1, and an overdose of 24 Gy on PTV field box 3D conformal radiation therapy technique treatment plan The 4FB.3DCRT plan was composed of 4-field box 18MV photons with apertures shaped to the planning target volumes PTVs in each beam's eyeview. The fields consisted of anterior, posterior and two opposing lateral fields. Field sizes were adjusted to ensure coverage of the PTVs with a margin in all directions to account for beam penumbra. All plans were normalized to cover 98% of the PTV with the 95% of the prescribed dose. Dose volume histograms (DVHs) were calculated for the PTV and OARs. As in 4FB.3DCRT planning, all plans were normalized to cover 98% of the PTV with 95% of the prescribed dose. The dose volume histograms (DVHs) were computed for the PTV and OARs. 3. Data Analysis and Statistical Study The dose volume histograms (DVHs) were computed for the PTV, prostate and the organs at risk. The dose conformity index and the inhomogeneity within the PTV were calculated and compared with 4FB.3DCRT and. The mean doses of the rectum, bladder and femoral heads were also compared between both the plans. The volume of the rectum and the bladder receiving 60 Gy and 70 Gy were computed and compared for 4FB.3CRT and by using the test of student method (the value p is significant p<=0.05). The fraction of the femoral heads volume receiving 40 GY and 50 GY were calculated and compared between 4FB.3DCRT and. 4. Results In this study, the mean of the PTV for 10 patients was cc (range cc cc). The isodose lines on an axial slice for 4FB.3DCRT and (10 fields as reference) are shown in Figs. 1 and 2, respectively. As seen in Fig. 1, 95% and 70% of the isodose lines approximate not only provide coverage of the PTV but also irradiate the neighboring normal critical structures. In contrast, the plan (Fig. 2) results in 95% and 70% of the isodose lines conforming to the shape of the PTV reducing the volume of the neighboring normal critical structures at the prescription dose Multi-enter 3D conformal radiation therapy technique treatment plan The plan was consisted of 10 fields 18MVas reference as follows: four fields on PTV1 (anterior, posterior and two opposing lateral fields), then 6 fields on PTV (two anterior oblique, two posterior oblique and two opposing lateral fields) with multi-leaf collimation for normal tissue sparing. The weights of the individual fields were optimized to maximize the dose uniformity in the PTV.

3 The African Review of Physics (2013) 8: Fig.1: Axial CT image with isodose distribution from the 3DCRT 4 field box plan superimposed. PTV is indicated in red. A dose of 70 Gy prescribed to point in PTV, with 98% of PTV covered by 95% of prescribed dose. Isodose lines indicated as follows: yellow, 100%; green, 95%; orange, 70%; pink, 50%; blue, 25% and cyan, and 10% isodose line. Fig.2: Axial CT image with isodose distribution from the 3DCRT multi-enters (10 fields) plan superimposed. PTV indicated red. A dose of 70 Gy prescribed to point in PTV, with 98% of PTV covered by 95% of prescribed dose. Isodose lines indicated as follows: yellow, 100%; green, 95%; orange, 70%; pink, 50%; blue, 25% and cyan, and 10% isodose line. The DVHs of the PTV volumes did not differ much between patients and no significant difference exists between the dose coverage of the prostate using 4FB.3DCRT and (Fig. 3). technique provided better the conformity index (Table 1).

4 The African Review of Physics (2013) 8: Fig. 3: PTV (red) and Prostate (magenta) DVHs for (dashed) and 4FB.3DCRT (solid). Table 1: The conformity and the inhomogeneity index for the both treatment plans. 4FB.3DCRT P Value Conformity Index Mean Inhomogeneity Index Mean Organs at risk The difference between the 4FB.3DCRT and plans is significant, for the DVHs of the OARs, rectum, bladder and femoral heads. DVHs of these volumes for both plans are shown in (Fig. 4).

5 The African Review of Physics (2013) 8: Fig.4: OARs DVH for both the techniques (dashed) and 4FB.3DCRT (solid). OARs indicated as follows: Yellow for bladder, blue for rectum and cyan for femoral heads Rectum and bladder An increase in the mean rectum and bladder dose is improved using the (Table 2). The rectum (bladder) dose was on the average Gy (57.57 Gy) and Gy (53.51 Gy) for 4FB and ME (10 fields as reference) 3DCRT, respectively. The mean percents of the rectum and bladder volumes receiving 60 Gy (V60), and 70 Gy (V70) for each patient with the both approaches were analyzed and the difference is statistically significant (Table 3). Table 2: The OARs mean doses of the all patients on function of the both techniques and 4FB.3DCRT. MEAN BLADDER DOSE (GY) MEAN RECT UM DOSE (GY) MEAN FEMORAL HEADS DOSE (GY) PAT IENTS P P P Average

6 The African Review of Physics (2013) 8: Table 3: Bladder and rectum comparison between V60 and V70 in both techniques. BLADDER RECT UM P P V60 (mean) 32.22% 38.67% % 42.27% 0 V70 (mean) 2.68% 6.89% % 4.57% 0.04 The percent rectum volumes received 60 Gy to 70 Gy (4FB.3DCRT, blue and, orange) Percent V60 V70 The percent bladder volum es received 60 Gy to 70 Gy (4FB.3DCRT, blue and, orange) Percent V60 These graphs show the decrease of the percents of the rectum and bladder volumes received 60 Gy and 70 Gy with the Femoral heads Compared 4FB.3DCRT, with the types of plans delivered lower doses to femoral heads (Table 2). The mean heads dose was on average Gy (range: Gy Gy ) and Gy (range: Gy Gy) for 4FB and ME (10 fields as reference) 3DCRT, respectively. The analysis of the percentage of the femoral heads volume received 40 Gy and 50 Gy (V40 and

7 The African Review of Physics (2013) 8: V50) yielded results consistent with the dosimetric analysis (Table 4). achieved a significantly lower dose to the femoral heads than the 4field box 3DCRT. Table 4: Femoral Heads comparison between V40 and V50 in and 4FB.3DCRT approaches. FEMORAL HEADS P V50 (mean) 0.19% 3.23% 0.05 V4 0 (mean) 4.21% 16.29% 0.05 The percent femoral heads volumes received 40 Gy to 50 Gy (4FB.3DCR, blue and, orange ) Percent V40 V50 The analysis of the mean volumes shows the decrease of the percentage of the femoral heads volumes receiving 40 Gy and 50 Gy using the approach. Furthermore, the dose delivered to the femoral heads also depending on the prostate volume. For the patients with prostate volumes exceeding 75 cc, the both treatment plans lead to an increase in the dose received by the femoral heads. Fig. 5 presents the femoral heads DVHs on function of the prostates volumes for the both approaches.

8 The African Review of Physics (2013) 8: Fig.5(a): Prostate volume = cc. Fig. 5(b): Prostate volume = cc.

9 The African Review of Physics (2013) 8: Fig.5(c): Prostate volume = cc. Fig.5: Example of femoral heads DVHs obtained with the both treatment plans 4FB.3DCRT (solid) and (dashed). Two morphologies of prostates are represented, a medium volume < 75 cc, and a large volume >75 cc. 5. Discussion Prostate cancer has become the most commonly diagnosed male malignancy in the west [2]. This suggests that more patients with prostate cancer will require treatment. Radiotherapy and surgery are the most important form of treatment in the curative management of localized prostate cancer. For men with high risk prostate cancer, the standard of safety is the radiotherapy in conjunction with androgen deprivation [3,4]. The role of WPRT in the management of high risk prostate cancer continues to be an area of controversy. The results of Radiation Therapy Oncology Group (RTOG) 9413 have suggested a broader implementation of WPRT for men with high-risk, clinically localized disease [5]. The use of WPRT for the initial phase of treatment appeared to provide a significant benefit in progression-free survival when it was delivered with neo-adjuvant and concurrent hormonal therapy [6,7]. In classic 3D conformal radiotherapy, it is common to use a four-field box, whole-pelvis plans, as primary phase of radiation and the typical pelvic dose is 45 or 46 Gy [6]. In the second phase of treatment, boost fields should include the prostate and the seminal vesicles, the total dose delivered is between 70 Gy and 78 Gy. Escalation of dose in prostate radiotherapy has increased the 6-year freedom from failure, including the biochemical PSA failure rates, from 64% using 70 Gy to 70% using 78 Gy [8]. In the context of escalation, the relative importance of WPRT for disease control is not clear. Another concern is the potential in increased morbidity associated with WPRT [9,10,11]. In our study, dose escalation has not been made. The optimal number of boost beams and the arrangement of these beams remain controversial. The first beams arrangement to be used is the four field technique, especially before the advent of multi-leaf collimator, because making the shielding block was laborious. With the emergence of multileaf collimator, beams arrangements using more than four fields have been proposed [12,13,14]. Fiorino et al compared three-, four-, and six-field techniques, and reported that the respective techniques were equivalent because sparing of the rectum was only achieved at the cost of femoral head irradiation [13]. Three fields have been more commonly used in the UK. A three-field coplanar conformal technique

10 The African Review of Physics (2013) 8: has been the standard treatment technique used at the Royal Marsden NHS Trust in the curative treatment of prostate cancer. A study in this institution, evaluating the three-field coplanar arrangements, showed that the one that provided the greatest rectal sparing was an anterior field with two opposing lateral fields [15]. Other investigators evaluated the benefit of using non-coplanar treatment plans [16,17,18]. Bedford et al. found that the use of non-coplanar beams in conformal prostate radiotherapy provides a small increase in rectal sparing [18]. In this study, two clinical treatment volumes were defined: prostate only (PO) and the prostate plus seminal vesicles (PSV). The rectal sparing was more significantly increased with PSV volumes than for PO volumes. It is clear that a variety of different techniques have been reported with differing results. Each technique has its peculiar advantages and disadvantages with respect to the degree of sparing of organs at risk, the ease of treatment set-up and delivery, and the treatment verification. Thus, treatment techniques vary greatly not only between cancer centers but also between countries, the choice however depending on the preferences of the treating clinician and physicist. The goal of our study was to evaluate the ability of the 10 fields as reference to reduce the volume of OARs (rectum, bladder and femoral heads) irradiated in men with high risk prostate cancer with whole pelvic irradiation in the first phase (46 Gy). Our results suggest that the is an effective means of limiting the volume of OARs irradiated in these patients. The analysis of the both approaches ( and 4FB.3DCRT) results show that with the the dose in OARs is lower, for example, 10,8% (11,98%) of the rectum (bladder) volume received 60 Gy, V70 on 0% (0,33%), and V74 on 0% (0%). From the statistical study of this work we deduce that the decrease of the dose in OARs is very important, which may reduce the risk of late sequel. The increase of the dose in the rectum and the bladder is due to a large part of them (rectum and bladder) being irradiated in the 4FB.3DCRT and the part which receives a high dose due to the antpost fields is usually smaller for the using the four oblique fields. We also deduced that the DVHs of the femoral heads vary considerable between the patients due to their different prostate volume not just between the treatment plans. Of the plans examined in this study, achieved the lower doses to the femoral heads, significantly the lowest for the patients with the smallest prostate volume. Several studies show that the 3DCRT static or dynamic in the prostate cancer decrease the dose in OARs [19,20,21,22]. In a work investigating the intensity-modulated radiotherapy (IMRT) strategy in dose escalation of prostate and pelvic lymph nodes, the authors concluded that the initial pelvic IMRT is the most important strategy in dose escalation and critical organ sparing [23,24 25,26]. The most important constraint of IMRT is the long treatment time [22,27]. Novel 3D conformal radiotherapy techniques aim to achieve intensity-modulated radiotherapy (IMRT)-quality radiotherapy plans with shorter treatment time. Rapid arc is a technique using arc radiotherapy. In a study, comparing the dosimetric quality and treatment efficiency of single-arc (SA) vs. double-arc (DA) and IMRT in the treatment of prostate cancer, DA achieved the best dosimetric quality with the highest minimum PTV dose, lowest hot spot, and the best homogeneity and conformity, with the lowest MU and shortest treatment time [28]. 6. Conclusion In the treatment planning for prostate cancer, produced dose distribution more favorable than could be achieved with 4FB.3DCRT. The multi-enters 3D conformal radiation therapy technique limits the irradiated volume of OARs, rectum, bladder and femoral heads, and allows the avoidance of the hot spots. Several questions remain to be answered. First, it is unclear whether 3DCRT modern techniques (IMRT, VMAT and others) are feasible in a busy clinic. Treatment planning and delivery are more time consuming than the classical technique. The most important question is whether dosimetric improvements seen in this study will translate into a reduced treatment sequel. References [1] David P. Dearnaley, Vincent S. Khoo, Andrew R. Norman, Lesley Mey, Alan Nahum, Diana Tait, John Yarnold and Alan Horwich. Lancet 353, 267 (1999). [2] V. J. Cogliano et al., J. Natl. Cancer Inst. 103, 1827 (2011). [3] M. Bolla et al., Lancet Oncol. 11, 1066 (2010). [4] A. V. D Amico et al., JAMA 280, 969 (1998).

11 The African Review of Physics (2013) 8: [5] M. Roach 3rd. et al., J. Clin. Oncol. 21, 1904 (2003). [6] Jonathan B. Ashman et al., Int. J. Radiation Oncology Biol. Phys. 63, No.3, 765 (2005). [7] M. Roach et al., J. Radiation Oncology Biol. Phys. 87, Issue 2, Supplement, 1 October, S106 (2013). [8] A. Pollack et al., Int. J. Radiat. Oncol. Biol. Phys. 53, 1097 (2002). [9] A. Pollack, J. Clin. Oncol. 21, 1899 (2003). [10] R. D. Ennis, J. Clin. Oncol. 22, 2254 (2004). [11] M. Roach 3rd. In reply [Letter]. J. Clin. Oncol. 22, 2255 (2004). [12] P. F. Akazawa et al., Radiother. Oncol. 41, 83 (1996). [13] C. Fiorino et al., Radiother. Oncol. 44, 251 (1997). [14] B. Lennernäs, G. Rikner, H. Letocha and S. Nilsson, Acta Oncol. 34, 953 (1995). [15] Vincent S. Khooa et al., Radiotherapy and Oncology 55, 31 (2000). [16] L. H. Marsh, R. K. Ten Haken and H. M. Sandler, Med. Dosim. 17, 123 (1992). [17] C. F. Mesina, R. Sharma, L. S. Rissman, L. Geering, T. He and J. D. Forman, Int. J. Radiat. Oncol. Biol. Phys. 30, 427 (1994). [18] James L. Bedford, Anthony J. Henrys, David P. Dearnaley and Vincent S. Khoo. Radiotherapy and Oncology 75, 287 (2005). [19] C. M. Nutting et al., Int. J. Radiat. Oncol. Biol. Phys. 48, 649 (2000). [20] J. B. Ashman, M. J. Zelefsky, M. S. Hunt, S. A. Leibel and Z. Fuks, Int. J. Radiat. Oncol. Biol. Phys. 63, 765 (2005). [21] Yu-Ming Liu et al., Int. J. Radiation Oncology Biol. Phys. 67, No.4, 1113 (2007). [22] David Palma, Emilly Vollans, Kery James, Sandy Nakona, Vitali Moissenko, Richora Shaffer, Michael Mckenzie, James Moris and Karl Otto, Int. J. Radiation Oncology Biol. Phys. 72, No.4, 996 (2008). [23] C. M. Nutting et al., Int. J. Radiat. Oncol. Biol. Phys. 48, 649 (2000). [24] M. J. Zelefsky, Z. Fuks and S. A. Leibel, Semin. Radiat. Oncol. 12, 29 (2002). [25] D. E. Heron et al., Gynecol. Oncol. 91, 39 (2003). [26] G. Luxton, S. L. Hancock and A. L. Boyer, Int. J. Radiation Oncol. Biol. Phys. 59, 267 (2004). [27] Henry C. K. Sze et al., Medical Dosimetry 37, Issue 1, 87 (2012). [28] K. Otto, M. Milette and J. Wu, Int. J. Radiat. Oncol. Biol. Phys. 2007, 69 (suppl.) S703 (2007). Received: 30 September, 2013 Accepted: 20 December, 2013