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1 Radiotherapy and Oncology 98 (2011) Contents lists available at ScienceDirect Radiotherapy and Oncology journal homepage: Prostate treatment planning Helical tomotherapy and intensity modulated proton therapy in the treatment of early stage prostate cancer: A treatment planning comparison Marco Schwarz a,, Alessio Pierelli b, Claudio Fiorino b, Francesco Fellin a, Giovanni Mauro Cattaneo b, Cesare Cozzarini b, Nadia Di Muzio b, Riccardo Calandrino b, Lamberto Widesott a a Agenzia Provinciale per la Protonterapia, Trento, Italy; b Istituto Scientifico S. Raffaele, Milano, Italy article info abstract Article history: Received 16 October 2009 Received in revised form 25 October 2010 Accepted 26 October 2010 Keywords: IMPT Tomotherapy Prostate Planning comparison Purpose: To compare helical tomotherapy (HT) and intensity modulated proton therapy (IMPT) on early stage prostate cancer treatments delivered with simultaneous integrated boost (SIB) in moderate hypofractionation. Material/methods: Eight patients treated with HT were replanned with two-field IMPT (2fIMPT) and fivefield IMPT (5fIMPT), using a small pencil beam size (3 mm sigma). The prescribed dose was 74.3 Gy in 28 fractions on PTV1 (prostate) and PTV2 (proximal seminal vesicles), 65.5 Gy on PTV3 (distal seminal vesicles) and on the overlap between rectum and PTVs. Results: IMPT and HT achieved similar target coverage and dose homogeneity, with 5fIMPT providing the best results. The conformity indexes of IMPT were significantly lower for PTV1+2 and PTV3. Above 65 Gy, HT and IMPT were equivalent in the rectum, while IMPT spared the bladder and the penile bulb from 0 to 70 Gy. From 0 up to 60 Gy, IMPT dosimetric values were (much) lower for all OARs except the femur heads, where HT was better than 2fIMPT in the Gy dose range. OARs mean doses were typically reduced by 30 50% by IMPT. NTCPs for the rectum were within 1% between the two techniques, except when the endpoint was stool frequency, where IMPT showed a small (though statistically significant) benefit. Conclusions: HT and IMPT produce similar dose distributions in the target volume. The current knowledge on dose effect relations does not allow to quantify the clinical impact of the large sparing of IMPT at medium-to-low doses. Ó 2010 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 98 (2011) Corresponding author. Address: Agenzia Provinciale per la Protonterapia, Via Perini 181, Trento, Italy. address: schwarz@atrep.it (M. Schwarz). Proton therapy is increasingly being used for the treatment of prostate cancer. Such treatments are typically delivered with two scattered proton beams, applying conventional dose prescription and fractionations schemes (e.g Gy in Gy per fraction) [1,2]. More aggressive, and technically difficult, treatment protocols may be beneficial: at least in selected cases, dose escalation in radiotherapy for prostate cancer improves the freedom from failure [3 5] and the combination of (a) very conformal IMRT dose distribution, (b) the fast adoption rate of IGRT and (c) the possibility that a/b of prostate cancer is low [6] produced a widespread interest towards hypofractionated regimens [7 9]. For such treatment approaches to be safe, dosimetric constraints have to be defined which are difficult to achieve with simple IMRT techniques or with scattered proton beams. The aim of this study is to assess whether proton therapy delivered with pencil beam scanning (PBS) can match, and possibly improve, helical tomotherapy (HT) dose distributions planned according to an hypofractionation protocol in clinical use for prostate cancer treatment. Material and methods We selected CT images and delineated contours of eight patients previously treated at Istituto Scientifico S. Raffaele (ISSR) with HT, according to an hypofractionated treatment protocol whose first results have recently been presented [10]. Volumes of interest and planning objectives For each patient, three Clinical Target Volumes (CTV) were defined: CTV1 (prostate), CTV2 (proximal third of the seminal vesicles) and CTV3 (distal two thirds of the seminal vesicles). Each CTV had a Planning Target Volume (PTV), generated as a 8 10 mm expansion of the CTV [11,12]; the dose prescription, defined as the median dose in the PTV, was 74.2 Gy for both PTV1 and PTV2 and 65.5 Gy for PTV3, to be delivered simultaneously in 28 fractions (i.e. 2.6 and 2.3 Gy/ fraction, respectively) Gy correspond to a 2 Gy/fraction equivalent of 88 Gy, 83.8 Gy and 74.2 Gy for an a/b of 1.5 Gy, 3 Gy and /$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi: /j.radonc

2 M. Schwarz et al. / Radiotherapy and Oncology 98 (2011) Gy, respectively. The planning objectives for PTV1, PTV2 and PTV3 required that at least 95% of the volume, and 98% when possible, received 95% of the prescribed dose; the maximum dose was set at 77 Gy for PTV1 and PTV2 and at 70 Gy for PTV3. A fourth prescription volume was defined where rectum and PTVs overlap; 98% of the overlap should receive at least 65 Gy, no more than 5% could receive more than 68 Gy and the maximum dose should be less than 70 Gy. The following organs at risk (OAR) were defined: rectum, bladder, bowel cavity, femur heads and penile bulb. According to the clinical protocol in use at ISSR, dose tolerances for the OARs were defined as follows: Rectum: (lower and upper bound indicate desired value and maximum acceptable value, respectively): volume receiving 50 Gy or more (V50) %, V %, V %, V %, dose to the hottest 1% (D1%) 670 Gy, D max (defined at one point): Gy; Bladder: V %, V %; Penile bulb: average dose Gy; Femur heads: V %, D max 6 45 Gy; Bowel: D max 6 55 Gy. According to the same protocol, for all OARs a reduction of the volume irradiated at lower doses than those explicitly defined was to be attempted but it did not have specific dosimetric objectives and it could not be obtained at the cost of violating other planning objectives. Planning techniques New tomotherapy plans were generated for this study. Values of modulation factors (3.0), pitch (0.287) and beam width (2.5 cm) were the same as in clinical practice [10,11]. These values were considered a good compromise between treatment quality and duration: treatments as those simulated here can be delivered in 4 5 min. Better results (in particular for penile bulb and bladder) are expected with tighter parameters, in particular with a 1- cm beam width, which should significantly improve the OAR sparing along the cranio-caudal direction [13,14]. Proton plans were designed in hyperion [15], an optimization module for photon and proton treatments. The proton plans, obtained through simultaneous optimization of the treatment fields assuming a PBS delivery mode, belong to 3D Intensity Modulated Proton Therapy (IMPT) as defined by Lomax [16]. We assumed that the Radio Biological Effectiveness (RBE) has a constant value of 1.1. For each patient, two IMPT plans were designed: the first (2fIMPT) had two opposed proton beams (90 and 270 gantry angles), which represents the field setup most commonly applied in proton therapy of the prostate; the second (5fIMPT) had five beam directions (45, 90, 180, 270 and 315 gantry angles), to investigate the benefit of adding beams in the IMPT plan. A pencil beam algorithm with heterogeneity and large-angle scatter correction was used for dose calculation [17]. The proton beam characteristics were: sigma_x = sigma_y = 3 mm at patient entrance (regardless of beam energy), initial energies of MeV, 4-mm water equivalent distance between energy layers and scanning pattern of 5 5 mm. A dose grid of mm was used for plan optimization and dose calculation. Plan evaluation The resulting dose distributions were imported for evaluation into VODCA (Medical Software Solutions, Hagendorn, CH), where DVHs were generated. Dose distributions were evaluated with the dosimetric indices of the cost function plus additional parameters. Normal tissue complication probability (NTCP) values for the rectum were calculated using the model parameters published by an Italian multi-centric study [18], M.D. Anderson in Houston [19], the Dutch dose escalation trial [20] and the University Hospital in T}ubingen [21]; these studies, when combined, represent clinical data for more than 3000 patients. When parameters were available, NTCP values were calculated for different patient categories (e.g. with or without previous abdominal surgery) and clinical endpoints (e.g. bleeding or stool frequency). In all these studies the Lyman Kutcher Burman NTCP model was used. As a consequence, each study produced an estimate for n (the volume effect parameter), TD50 (the dose corresponding to 50% probability of complication) and m, the steepness of the dose response curves. It is worth noticing that, while the values of TD50 and m varied from study to study, the n value was very similar when the end point was rectal bleeding, ranging from 0.08 to In total, seven NTCP values were calculated for each dose distribution. Statistical significance of the differences between the two plans was assessed with a Wilcoxon test (threshold for significance of 0.05). Results Target volumes In general, HT and IMPT produced very homogeneous dose distribution in the PTVs, mostly complying with all planning objectives (see Fig. 1). A summary of the dose parameters values for the PTVs is shown in Table 1. More in detail: The most important target coverage parameter, i.e. V95%, was satisfied by both HT and IMPT techniques with one exception: for PTV2, HT missed the planning objective by 1% or more in three patients. Even in this case, however, the value of V95% averaged over all patients essentially met the constraint (94.7% vs 95%). The value of V98% showed larger differences among the techniques, with HT reaching very good results in PTV3. For PTV1 and PTV2, V107% was kept to 0% of the volume for all patients and both techniques and the differences in D max were typically within 1 Gy. Somewhat larger differences were found for V107% and D max in PTV3, in favour of both IMPT techniques (p > 0.05). The conformity index (CI) [22] was better in IMPT dose distributions: for PTV1+2, the average CI was 1.3 for IMPT and 1.7 for HT (p < 0.01), for PTV3 it was 1.5 for IMPT vs. 2 for HT (p < 0.01). Both IMPT and HT were very conformal posteriorly to the target, at the interface between PTV and rectum, but IMPT had a superior conformity anteriorly, cranially and caudally (see Fig. 2). Organs at risk In most cases, HT and IMPT plans complied with all OARs dose volume objectives (see e.g. Table 2 for the rectum). The only exception is D max in the rectum (defined as dose in one point), which was missed in most cases: HT could meet the target value (72 Gy) in one out of eight cases, 2fIMPT and 5fIMPT in two. The average rectum DVH is shown in Fig. 1, while Fig. 3 illustrates the DVHs of bladder and femur heads. In general, the lower the dose the larger the difference in favour of IMPT: for a dose of about a third of the prescription, IMPT reduced the irradiated volume by 35 50%, while for doses around 50% of the prescription the reduction was between 25% and 40%; the advantage of IMPT then further decreases and tends to vanish for doses of % of the prescribed dose, where HT plans achieved better results in a few cases.

3 76 Helical tomotherapy and intensity modulated proton therapy Fig. 1. Average DVH of PTV1 and rectum over the eight patients for the three irradiation techniques compared in this study. Table 1 Average target volumes dose parameters for the dosimetric indices that were included in the cost function. Median and D max are in Gy, V95% and V98% are in percentage. Median V95% V98% D max PTV1 HT fIMPT fIMPT PTV2 HT fIMPT fIMPT PTV3 HT fIMPT fIMPT Overlap HT fIMPT fIMPT Legend: HT, helical tomotherapy; IMPT2f, 2-field intensity modulated proton therapy; IMPT5f, 5-field intensity modulated proton therapy; D max, maximum dose. Rectum Table 2 summarizes the dosimetric values achieved for the rectum by the three techniques. On average, V60 and V65 for all techniques were below the minimum of the allowed dose range (i.e. 35%, 25% and 15% of the volume, respectively). All values up to V60 showed a statistically significant difference in favour of IMPT. V65, V70, D1% and D max had similar values for the three techniques, though 5fIMPT achieved the best results. For all patients, techniques and NTCP parameters set, the NTCP values were lower than 5%, except when analyzed with the data from Rancati et al. [18] and Tucker et al. [19]. According to these fits, both having G2 G3 late rectal bleeding as the endpoint, the complication probabilities were typically between 7% and 10%. The average difference in NTCP values between HT and IMPT was always less than 1%, regardless of the parameter set used to calculate the NTCP. In one case, i.e. the estimation of stool frequency according to the fit by Peeters et al. [20] (n = 0.39), the difference between HT and IMPT was statistically different, in favour of IMPT. The average NTCP was, however, very low in both cases (2.5% vs. 1.9%). Bladder IMPT allowed a statistically significant reduction of the volume irradiated from 0 Gy up to high doses; for instance, 2fIMPT reduced from 29% to 21% the average volume of bladder receiving 60 Gy or more. The average bladder mean dose went from 40.4 Gy with HT to 22.2 Gy with IMPT (p < 0.01). HT had smaller maximum doses than IMPT (76.1 Gy vs. 77, p = <0.01). Femur heads The planning objectives were easily met by all techniques. The best results were obtained by 5fIMPT and the worst by 2fIMPT (see Fig. 3), but all three techniques kept the femur heads irradiation at low levels, achieving an average value of V40 below 0.5%. Penile bulb IMPT techniques allowed a large reduction of the mean dose (average values from 45.5 to 24 Gy for 2fIMPT, p < 0.01) and V50 (average values from 44% to 20% for 2fIMPT, p = 0.01). Bowel cavity All techniques achieved a low level of irradiation of this OAR. Among the parameters used for the comparison, only D1% and D max have non negligible values: in both cases IMPT achieves a statistically significant dose reduction, by 20 and 10 Gy, respectively. Unspecified normal tissues Fig. 4 shows the difference between HT and 2fIMPT in whole body dose: below Gy, 2fIMPT allows a sparing ranging from 1000 cc to more than cc; above 25 Gy, 2fIMPT continues to spare the normal tissue, but to a less extent.

4 M. Schwarz et al. / Radiotherapy and Oncology 98 (2011) Fig. 2. HT and IMPT dose distributions on three orthogonal planes. Discussion Planning studies have been published between IMRT and proton therapy either comparing static-field IMRT and HT vs. IMPT in phantoms [23], or creating scattered beams (e.g. [1,24]) or PBS [25 27] dose distributions to evaluate the benefit of protons in prostate cancer treatment with respect to linac-based IMRT. Several proton therapy centers with the capability of delivering PBS treatment are expected to start their activity in the next years. Pencil beam scanning is an attractive proton beam delivery modality thanks to both its dosimetric advantages (better proximal dose conformality, the possibility of delivering 3-D IMPT treatments and reduced neutron dose) and operational improvements, as it does not require patient specific hardware. It is therefore worth analyzing how PBS dose distributions compare against plans that can be delivered with a complex IMRT technique such as HT. This is the first study comparing HT and IMPT dose distributions on real patient anatomies in the treatment of prostate cancer with simultaneous integrated boost on a clinically applied moderate hypofractionation protocol. Target volumes The differences between HT and IMPT dose distributions were mostly marginal. In one case (V95% for PTV2) differences were of potential clinical interest, but they concerned a parameter of the cost function where even the technique providing inferior results (HT) did essentially meet the protocol requirement. The planning protocol required a maximum dose (defined in one point) of no more than 77 Gy (104% of the prescribed dose), thus being more strict than the ICRU requirements. High dose homogeneity in the target is a characteristic often found in HT dose distributions. Our results show that the same dose homogeneity can be achieved with two IMPT proton fields, when small pencil beams are used. Organs at risk Although the differences between HT and IMPT in the OARs vary from organ to organ (see Figs. 1 and 3), some general properties can be identified: Table 2 HT, 2-field IMPT and 5-field IMPT 5 dose parameters for the rectum, averaged on the eight patients included in this study. The range of values among patients is shown in parenthesis. D mean, D1% and D max are in Gy, the remaining values are in percentage. In the first column, the values in italic show the dose parameters included in the cost function and in parenthesis the value that was aimed at in the optimization. HT 2f IMPT 5f IMPT D mean 36.5 ( ) 25.0 ( ) 27.3 ( ) V ( ) 44.0 ( ) 46.6 ( ) V ( ) 31.9 ( ) 30.0 ( ) V50 (635 45%) 30.4 ( ) 26.5 ( ) 24.0 ( ) V60 (625 30%) 20.9 ( ) 19.5 ( ) 17.4 ( ) V65 (615 20%) 14.6 ( ) 13.9 ( ) 13.0 ( ) V70 (61 3%) 1.2 ( ) 1.2 (0 3.4) 0.5 ( ) D1% (670 Gy) 70.3 ( ) 69.6 ( ) 68.9 ( ) D max ( Gy) 73.3 ( ) 73.2 ( ) 72.7 ( ) (1) For doses above 65 Gy, HT and IMPT produce very similar results, with 5fIMPT being marginally better. IMPT dose distributions have superior dose conformity; this superiority, however, translates in better dose sparing at high doses for only one OARs, i.e. the bladder. In other words, HT achieves very high dose conformity in specific regions, e.g. where the rectum and the target volumes are in close proximity, while IMPT produces very conformal dose distributions all around the PTVs (see Fig. 2). (2) The dose level where IMPT and HT DVH start separating one another, and where the differences in favor of IMPT become apparent, is organ-specific, ranging from 65 to 70 Gy in the bladder and penile bulb to 55 Gy in the rectum. Below 65 Gy, all dose parameters except D max and D1% of the femur heads show a statistically significant superiority of both IMPT techniques. The results we obtained for bladder and penile bulb, where IMPT is better than HT essentially over the whole dose range, suggest that the statement that protons are better than state-of-the-art photons only at low doses is not a general rule. (3) For doses below 40 Gy, the results are better evaluated comparing the irradiated tissues as a whole rather than every single organ (see Fig. 4). The sparing allowed by proton therapy is very large for doses up to Gy. Between 25 and

5 78 Helical tomotherapy and intensity modulated proton therapy Fig. 3. Average DVH of bladder and femur heads over the eight patients for the three irradiation techniques compared in this study. Fig. 4. Difference in dose to the whole body (i.e. target and OARs included) between HT and 2fIMPT in the dose range between 0 and 20 Gy. Volumes are in cc. In the smaller box, the values above 25 Gy are shown at a different scale. 40 Gy, the sparing is more moderate, but still in the range of 200 cc. The femur dose appears not to be a concern even for 2fIMPT. For the OARs considered in this study, current clinical data suggest a correlation between mean organ dose and an organ-specific endpoint only for the rectum [28]. Beside that, a dramatic reduction of the dose bath is associated to a decreased risk of radiation-induced cancer [29]. Rectum The high dose planning objectives for the rectum were the most difficult to meet, as the rectum is included in a PTV, but at the same time strict constraints are set on D1% and D max. Except for one case (the risk for stool frequency estimated by Peters et al. [20]), all NTCP parameters set had a value of n (the volume-effect parameter) between 0.08 and This range of values makes the EUD (and therefore the associated NTCP) strongly influenced by the rectal volume receiving high doses. Since in the high dose region IMPT and HT plans are very similar, so are the NTCP estimates. When frequency is the endpoint in the NTCP fit, the n value is higher (0.39) [20], thus making the intermediate and low dose range more important in determining the risk of complications. This explains why for this endpoint a statistically significant difference was found in favour of IMPT, although both techniques are associated to a small risk of complication.

6 M. Schwarz et al. / Radiotherapy and Oncology 98 (2011) IMPT decreased the average mean dose to the rectum by 9 12 Gy. A multivariate analysis based on 3D-CRT data found the mean rectal dose as the best predictor of acute gastrointestinal toxicity [28]. According to this result, HT and IMPT should be associated with about 18% and no more than 13% Grade P2 acute toxicity, respectively. The study by Vavassori et al., however, does not include a complete volumetric dose response analysis, so it is unclear to what extent their results could be applied to HT and IMPT. Bladder, penile bulb and femur heads For bladder and penile bulb, IMPT plans show a superiority over the whole dose range; the only exception is the maximum dose, typically lower in HT by 1 Gy. From 70 Gy downwards, all dose parameters show a statistically significant superiority of IMPT, which nearly halved the average dose in both OARs. The relatively poor result obtained by HT in the penile bulb is not unexpected [13,30], and it is caused by a feature in HT delivery producing a shallow gradient along the couch motion direction. A 1-cm field width and/or a longitudinal motion of the distal jaw, which at the moment is not implemented in HT, may in the future help obtaining better results also at high doses in both the penile bulb and the bladder. The clinical data on late effects for bladder and penile bulb irradiation do not allow to estimate the clinical benefit associated with this sparing. On the one hand, it is reasonable to expect that reducing V60 of the bladder by about a third, or more than halving V50 of the penile bulb, could lead to clinically measurable effects in a patient population. On the other hand, current clinical data suggest a small volume effect of the bladder when severe late toxicities are considered [31], thus emphasizing the role of the high dose region, where IMPT has a smaller advantage over HT. Concerning the penile bulb, the dose values obtained by HT are already below the thresholds currently suggested to decrease the risk of erectile disfunction [32]. Concerning the femur heads, even the technique with the worst results, i.e. 2fIMPT, is safely below the dose thresholds typically associated to a risk of complications. 2f vs 5f IMPT Beside a slightly increased normal tissue irradiation at low doses with respect to 2fIMPT, 5fIMPT is superior to both 2fIMPT and HT for all volumes of interest. Therefore, if the best overall technique has to be chosen based on dosimetric parameters only, this is 5fIMPT. On the other hand, 2fIMPT is quick and simple to apply (strictly speaking it does not even require a gantry) and it does create plans at least as good as HT dose distributions in the high dose region, while significantly improving the medium-to-low dose region. Neither 2fIMPT nor 5fIMPT relies on the distal dose fall-off to spare the rectum, so in terms of plan robustness they should not be significantly different. How general are these results? Planning protocol. Prostate cancer patients are routinely treated at S. Raffaele with HT based on the dosimetric protocol used in this study, which, as every treatment protocol, is to some extent tailored to the technical characteristics of the device used for treating patients. We can therefore say that this study, rather than being a comparison of two techniques based on neutral treatment prescriptions, was de facto assessing whether IMPT could first reproduce and then improve the dosimetric results of the reference treatment approach, i.e. HT. For instance: (a) The maximum dose allowed in PTV1-2 (77 Gy) is less than 104% of the prescribed dose: such tight constraint allows taking full benefit of one feature of HT, i.e. the capability of generating highly homogeneous dose distributions in the targets. One could wonder whether by slightly relaxing this requirement other dosimetric parameters could be improved, e.g. the maximum dose in the rectum. (b) Most planning objectives are defined for doses higher than 50 Gy and none for doses lower than 40 Gy; this reflects the characteristics of photon therapy plans, where the volume of tissue receiving medium to low doses is mostly a by-product of the treatment approach (e.g. the number of fields or arcs, the use of HT as opposed to linac-based IMRT, etc.), and it can hardly be controlled in the optimization. A treatment protocol tailored to IMPT would probably be different, e.g. by setting objectives in terms of mean OAR doses that would be unachievable for photon techniques. Optimization modules. Hyperion and the HT treatment planning system have different approaches to plan optimization. In particular: (1) hyperion uses constrained optimization, where ( hard ) constraints are set for the OARs, while Tomotherapy TPS works with weighted objectives for both targets and OARs; (2) several dose effect models can be used to define a cost function in hyperion [33], while tomotherapy cost functions are based on dose volume histogram (DVH) points only. Although hyperion provides more flexibility in defining the cost function, the dosimetric protocol was entirely expressed in terms of DVH points, so it is difficult to say to what extent the use of two different optimization approaches affected the results. IMPT planning technique. The field set-up is clinically realistic; from the point of view of plan robustness, it is necessary that the presence of air pockets in the rectum is appropriately handled during planning and the shape changes of rectum and bladder along the course of treatment are tracked and corrected for [34]. It has been proven that patient preparation, also through dietary requirements, helps reducing variability in the rectum volume [12,35]. Another option is the use of a rectal balloon (e.g. [36]). We assumed the possibility of using a small proton pencil beam size. This size has not been achieved yet in clinical practice but, at least for the deep ranges needed to treat prostate cancer, it has been measured in proton therapy systems currently under testing 1 and it is expected to be available in the near future at several centres, including the one in Trento. Conclusion In this study, HT and IMPT were found to produce equivalent dose distributions in the target volumes, though 5-field IMPT provides the best results overall. IMPT dose distributions in the OARs are superior for doses from 0 to 60 Gy at least, in particular in the bladder and penile bulb, with a large benefit at lower doses. The probability of late gastrointestinal complications, according to the NTCP estimates, are very similar for HT and IMPT. Acknowledgments CT data, contours and dose distributions used in this study are available upon request to the corresponding author. 1 See e.g. Safai et al., Is collimation really necessary to improve the penumbra of a scanned proton beam at shallow depths?, presented as a poster at PTCOG 49, 2010.

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