Helical tomotherapy-based hypofractionated radiotherapy for prostate cancer: A report on the procedure, dosimetry and preliminary clinical outcome

[Downloaded free from http://www.cancerjournal.net on Monday, June 17, 2013, IP: 115.240.61.44] Click here to download free Android application for this journa Original Article Helical tomotherapy-based hypofractionated radiotherapy for prostate cancer: A report on the procedure, dosimetry and preliminary clinical outcome ABSTRACT Context: Hypofractionated intensity-modulated radiotherapy (IMRT) under image guidance using helical tomotherapy for prostate cancer improves therapeutic ratio. Aims: To report on clinical and dosimetric experience using hypofractionated helical tomotherapy for prostate cancer. Settings and Design: Prospective consecutive case series as feasibility study approved by Institutional Review Board (IRB) (2007-11). Materials and Methods: The staging work-up, risk stratification, simulation, contouring, planning, online matching and treatment delivery methodology are described in detail. The doses to (prostate and nodal) PTV and organs at risk (bladder, rectum, bowel and femoral heads) are described. The audit of online matching was used to determine set-up errors, PTV margins and resultant translational vector. We also report the outcomes in terms of biochemical relapse-free survival and acute toxicity. Results: Fifty-three consecutive patients were included. The baseline PSA was 23 ng/ml (1.60-100.37). The prostate BED3 ranged from 110-129 Gy (a/b for prostate 1.5-3 Gy) and nodal 72-87.68 Gy. The required PTV margin by van Hark s formula for lateral, longitudinal and vertical axes were 11.30, 9.95 and 13.49 mm, respectively with resultant vectors 3-15 mm. There was 7% to 8% chance of missing part of CTV in absence of image guidance. There was only one patient requiring premature conclusion at 45 Gy due grade 3 genitourinary toxicity. At median follow-up of 23 months, biochemical relapse-free survival rate is 95.2%. Conclusions: Hypofractionated IMRT under image guidance using helical tomotherapy for prostate cancer is feasible with acceptable acute toxicity and may be advantageous in high throughput centers. KEY WORDS: Helical tomotherapy, hypofractionated, intensity-modulated radiotherapy, prostate cancer INTRODUCTION Radiotherapy for prostate cancer is in an exciting and challenging era. It has benefitted from advances in imaging and technology for both diagnostic and therapeutic improvement. Evidence for improvement in therapeutic ratio over the last decade has come in the form of randomized trials. [1-5] Use of conformal radiotherapy techniques has shown superiority over conventional radiotherapy methods in reducing late rectal toxicity, which remains the dose-limiting organ at risk in prostate external beam radiotherapy. [6-8] A number of randomized trials have shown to improve the control of prostate cancer using higher doses as compared to conventional doses using prostate-speciûc antigen (PSA) as a surrogate end point. These trials have shown an improvement in biochemical control rates between 6% and 19% by raising the radiation doses from 64-70 Gy to 74-78 Gy. Dose Journal of Cancer Research and Therapeutics - April-June 2013 - Volume 9 - Issue 2 escalation has however come at a cost of significant increase in clinically relevant late rectal toxicity. [9,10] Intensity-modulated radiotherapy (IMRT) can offer the potential to reduce rectal toxicity. [11] This has been shown in a prospective, but not randomized, series of over 770 patients treated at the Memorial Sloan Kettering Cancer Center. [6] Traditionally, the a/b ratio (where a and b are the linear and quadratic components, respectively, of the cell kill) of 10 Gy is used to calculate the biologically equivalent dose for acute toxicity and tumor response. Recently several investigators have alluded to the fact that prostate cancer may have a high fractionation sensitivity due to a low a/b ratio of around 1.2-1.5. [12] On the other hand, it has been suggested that the rectum, which is the dose-limiting organ in prostate radiotherapy, has a/b ratio of between 3.6 and Vedang Murthy, Rahul Krishnatry, Suman Mallik, Zubin Master, Umesh Mahantshetty, Shyamkishore Shrivastava Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, India For correspondence: Dr. Vedang Murthy, Department of Radiation Oncology, Advanced Center for Treatment Research and Education in Cancer (ACTREC), Sector 22, Kharghar, Navi Mumbai, India. E-mail: vedangmurthy@gmail. com Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.113378 PMID: ***** Quick Response Code: 253

6.0. [12] If this difference is truly present, there is potential to escalate the total biological doses by using hypofractionated schedules with acceptable rectal toxicity and shorter overall treatment duration. Using large dose fractions with tight margins as used in IMRT raises the risk of under dosage of the target with every fraction due to potential internal prostate motion. The prostate moves internally in response to variations in rectal and, to some extent, bladder filling. [13] Solutions to correct the position of the gland before treatment include ultrasound guidance, fiducial marker implantation and daily computed tomography (CT) imaging. [14-16] Helical tomotherapy (HT) is one such technology platform to deliver IMRT with 3D image guidance capability. It uses a 6-MV linear accelerator mounted on a slip-ring CT gantry that delivers radiation helically, using a modulated fan beam. The fan beam is modulated as a function of the gantry angle by a 64-leaf binary MLC. Due to the large number of beam angles used per gantry rotation (a 360º circle, which is modulated at 7º intervals) and the small open-close time of the MLC leaves (20 ms to open or close), a very high level of intensity modulation can be achieved. An onboard CT detector is used for acquiring megavoltage CT (MVCT) images, giving the system image guidance capabilities. This is a report on the clinical and dosimetric experience for patients with prostate cancer treated using hypofractionated regimen on HT. MATERIALS AND METHODS The primary objective of the current report was to investigate the feasibility of delivering hypofractionated IMRT with MVCT-based image guidance and to document dosimetric, treatment delivery and acute toxicity parameters. Patients were treated as part of a prospective feasibility study approved by the Institutional Review Board (IRB) after written informed consent. The study cohort included 53 patients of adenocarcinoma of the prostate, registered at the centre from November 2007 to April 2011. Patient evaluation included a detailed history and complete physical examination. Baseline blood studies included baseline complete blood counts and standard biochemistry tests. A PSA level was obtained for each patient within 6 weeks of registration. Staging investigations included a bone scan, and CT scan of the chest abdomen and pelvis. An MRI of the pelvis was also done in case the seminal vesicles were not clinically involved. Patients with involvement of SV on MRI were treated as T3b. All patients had newly diagnosed low, intermediate or high risk prostatic adenocarcinoma. Low risk was defined as PSA <10 ng/ml or Gleason score 6; intermediate risk was defined as PSA 11-20 or Gleason score 7 and high risk group was defined as ct3b-t4, PSA > 20 or Gleason score 8-10 based on the Roche formula. [17] None of the patients had received any radiotherapy prior to accrual or had any evidence of distant metastasis. Hormone therapy for intermediate and high risk patients was given in the form of LHRH analog and an antiandrogen in the first 3-4 weeks to prevent testosterone flare. The LHRH analog was continued during radiotherapy and later for a period of 6 months to 24 months depending on the risk grouping. The general characteristics of the patients are shown in Table 1. Radiotherapy planning preparation and contouring have been previously described. [18] Briefly, the following steps were performed consistently for all patients and target/oar delineation was approved by a single physician (VM). Patient preparation Bowel preparation: Specific steps such as use of laxatives or self-administered enema were not used for bowel preparation. Patients were however instructed to empty their bowel before the planning CT scan and each treatment. Bladder filling protocol: We followed a predefined bladder filling protocol to achieve a comfortably full bladder and all patients were asked to void completely and to drink 500 ml Table 1: Patient characteristics Age (years) 65.2 (mean) (SD 7.69) 67 (median) 45-80 (range) Symptom duration (months) 8 (median), 13 (mean) PSA (ng/ml) At presentation 23 (median), 1.60 to 100.37 (range) Last follow-up 0.11 (median), 0.001 to 22.037 (range) Gleason s score Number (%) 6 9 (17%) 7 25 (47%) 8 11 (21%) 9 7 (13%) 10 1(2%) TNM stage Number T1c 2 T2a 4 T2b 11 T2c 4 T3a 9 T3b 23 N1 9 Risk group (RTOG) Number Low risk 1 Intermediate risk 8 High risk 44 Median duration of hormone therapy 9 months (among those who have finished) Median duration between hormone 3 months; 0-14 (ranges) therapy and RT starting Radiotherapy duration 38 days (median), 38 days (mean); 13 (SD) Median follow-up 23 months 254 Journal of Cancer Research and Therapeutics - April-June 2013 - Volume 9 - Issue 2

of plain water 45 minutes prior to acquiring the CT scan. This protocol of bladder filling was followed daily during treatment to displace bowel from high dose regions and minimize displacement of prostate due to variable bladder filling. Patients were simulated in supine position with hands over chest and a knee rest in place. Three fiducial markers were placed over skin at laser intersections; one at symphysis pubis and two laterally at the lateral aspect of thighs. CT simulation was performed on a 4-slice CT scanner ( Somatom, Siemens, USA). Contrast-enhanced CT scans were taken from 1 st lumbar vertebra to 5 cm inferior to the ischial tuberosity, with a slice thickness of 3 mm. Laser marks were permanently tattooed for further setup during treatment and those were considered as setup points. Volume delineation was done on the Coherence Dosimetrist workstation (Ver.2.2.130, Siemens Medical Solutions, USA). For consistency, all the contours were checked and finalized by a single radiation oncologist (VM). For patients without clinical or radiological involvement of SV, the whole of prostate gland including any ECE and the base of seminal vesicles defined as the proximal 0.5 cm of the SV was delineated as the CTV. [19] The distal, uninvolved SV was included in the pelvic nodal volume as described below. For patients with SV involved by disease (T3b), entire prostate and whole of the seminal vesicles were included in the CTV. Although MRI coregistration was not done, the apex of prostate was identified carefully from the diagnostic MR images. A 3D margin of 7 mm was grown in all directions except the posterior rectal interface to where it was kept at 5 mm to generate the PTV. All except 8 patients received pelvic nodal irradiation in addition to the prostate and SV. The prophylactic lymph nodal delineations follow the pattern shown in the RTOG website. [20] Briefly, contouring of nodal CTV started from the level of bifurcation of common iliac vessels i.e. usually at L5-S1 junction. Contouring included the common iliac vessels for patients with the presence of gross nodal disease in the pelvis. Contour was drawn around the major vessels with margins of about 5 mm and then modified depending on the anatomical boundaries like bone, muscles and peritoneum. The external iliac contouring was stopped at the top level of the femoral head and the femorals were not contoured. The upper external iliac region delineation also included the lateral and medial pre-sacral nodal area from S1-3 with a thickness of 8-10 mm from the anterior sacral wall. The internal iliac lymph node contouring (including the obturator node) was stopped at the beginning of the obturator foramen. The caudal part of the volume included the distal part of the SV when it was uninvolved clinico-radiologically. In the two patients in whom there was radiological evidence of lymph node involvement, the node was contoured according to its pre-hormonal size and a PTV of 5 mm was grown. A 3D volumetric margin of 7 mm was grown all around the prophylactic and gross nodal CTV to generate the respective nodal PTV. A 1 cm thick shell volume was created 5 mm away and around the PTVs to control the dose spillage beyond the targets, improve dose conformity and have a sharper dose fall off. Among the organs at risk, rectum was contoured as a solid structure starting from the recto sigmoid flexure up to the bottom of ischial tuberosity. The rectal wall was not drawn separately. The entire bladder was contoured as a solid structure from the dome to the base including the wall. Bowel was represented by a single solid structure encompassing the peritoneal cavity and any loops of bowel in the pelvis. The upper extent was kept constant at 5 cm superior to the uppermost extent of the pelvic nodal PTV to have comparability of the dose volume data. Penile bulb was drawn carefully on the CT image below the pelvic diaphragm with reference to the MRI of pelvis. Both femoral heads were drawn within the acetabulum without including the neck of the femur. All image and volume datasets were transferred to the proprietary tomotherapy treatment planning station (version 2.2.4, Tomotherapy Inc., USA) for inverse planning. Planning was done as a single phase Simultaneous Integrated Boost (SIB) technique. The tomotherapy planning system uses a convolution-superposition algorithm for dose calculation and a least squares minimization function for optimization during inverse planning. Treatment planning parameters unique to tomotherapy are field width, pitch and modulation factor. The field width is the thickness of the fan beam selected for treatment. Most HT units are commissioned with three clinical field widths (1 cm, 2.5 cm and 5 cm). The pitch is the distance traveled by the couch per gantry rotation as a fraction of the field width. The modulation factor is the ratio between maximum and average beam intensity and determines the speed of gantry rotation, and all these parameters have been explained in depth in other publications. [21] For all cases, a field width of 2.5 cm, pitch of 0.3 and maximum modulation factor of 3-3.5 was used during optimization. Due to the nature of the feasibility study and the associated initial learning curve, the prescribed dose to prostate and nodal volume varied progressively. However, the different regimen used had relatively equivalent biologic effective dose (BED) as shown in Table 2 (a/b for prostate 1.5 to 3 Gy; the 2 Gy equivalent doses calculated). The prostate BED3 ranged from 110 to 129.7Gy and for nodal region 72 to 87.68 Gy. We started with usual conventional dose to prostate from 66 Gy/33# with 2 Gy per # and this was followed by dose escalation to 74 Gy/35#. As no grade 3 acute GI or GU toxicity were observed, we moved to hypofractionated schedules from 2.64 Gy, 2.5 Gy and 2.0 Gy per fraction with BED Gy3 124.08, 114.6 and 110 Gy 3 respectively. The pelvic CTV dose per fraction was also changed from 1.57 to 2.25 Gy per fraction accordingly [Table 2]. Journal of Cancer Research and Therapeutics - April-June 2013 - Volume 9 - Issue 2 255

Table 2: Equivalent Dose Dose Number BED 10 BED 3 BED 1.5 EQD2 10 EQD2 3 EQD2 1.5 PTV prostate 74 Gy/37# 5 88.80 123.33 172.67 74.00 74.00 74.00 60 Gy/20# 17 78.00 120.00 180.00 65.00 72.00 77.14 66 Gy/25# 10 83.42 124.08 182.16 69.52 74.45 78.07 62.5 Gy/25 4 78.13 114.6 166.7 65.1 68.75 71.43 66 Gy/33# 4 79.2 110 154 66 66 66 68 Gy/25# 11 86.5 129.7 191.3 72.08 77.79 81.99 70 Gy/35# 2 84.00 116.67 163.33 70.00 70.00 70.00 PTV node 50 Gy/25# 20 53.10 72 99.00 44.25 43.2 42.43 45 Gy/20# 15 55.12 78.75 112.50 45.94 47.25 48.21 55 Gy/37# 4 63.34 82.51 109.89 52.79 49.51 47.10 55 Gy/35# 2 63.58 83.71 112.5 52.98 50.22 48.2 56 Gy/33# 4 65.5 87.68 119.4 54.59 52.61 51.15 The main focus during planning was achieving acceptable target coverage with optimal organ sparing. For PTV, the goal was to deliver more than 95% of the prescribed dose to 100% of the volume, while keeping dose homogeneity as high as possible. For the rectum and bladder, the planner started by reducing the dose in the high dose regions of the DVH then in the intermediate and low dose regions as far as possible while maintaining the PTV coverage. The constraints for OAR in hypofractionated regimen were appropriately scaled down based on the Linear Quadratic Model. [22] Due to the complexity of Tomotherapy treatments, a patient specific QA or a Delivery (DQA) is performed for every treatment plan (similar to IMRT QA for conventional IMRT). A DQA procedure involves delivering the treatment to a cheese phantom and assessing the dose delivered by various means. A DQA plan is prepared where the dose distribution delivered by the particular treatment plan is recalculated on the phantom. When the treatment procedure is delivered to the phantom, measurements are made within the phantom using film (either EDR2 or GAF Chromic film) and an ion chamber (A1SL). These measurements are compared with the values from the calculated dose distribution and should be within a tolerance of ± 3% (for film, the tolerance criteria used is a gamma value of 3% Dose difference and 3 mm distance-toagreement). A more detailed description of the DQA procedure has been previously reported. [22] After following the bladder filling protocol as described above, patients were set up on the treatment unit aligned with the tattoos and daily imaging was performed for setup verification, using the onboard MVCT. The MVCT images and the KVCT (kilo-voltage CT) planning images were first auto coregistered by using bone and soft tissue matching technique and a fine resolution setting. After automatic matching, fine manual adjustments were done using direct visualization of the prostate by the oncologist for all fractions. Translational shifts (in mm) were recorded as a combination of this 2 step process in lateral, longitudinal and vertical directions and rotational shifts (roll, pitch and yaw) were recorded in degrees. All fractions were corrected on the basis of final online matching. Patients were repositioned if any of the uncorrectable rotational error (i.e., pitch and yaw) were more than 2 degrees. Patients were followed up with clinical examination and PSA testing every three months for the first year along with toxicity assessment. Imaging was only done if clinically indicated. Biochemical failure was defined according to the revised ASTRO definition (Phoenix) of at least 2 ng/ml greater than the nadir PSA. [23] Statistical data was analyzed using Statistical Package for Social Sciences (SPSS) version 15.0. Mean values are indicated with standard deviation or 95% confidence interval. Events were calculated from the date of diagnosis (HPR confirmation) to the day of event. Plans were assessed by dose volume histogram analyses and visual interpretation of isodoses in transverse, sagittal and coronal views. V 95% (percentage volume of target receiving at least 95% of the prescribed dose), V 105%, D 5% (dose in Gy, received by 5% of the target volume), D 95%, D 99% (representing underdosage within the target) and D 1% (representing areas of high dose in the target) were checked for target. Homogeneity index and conformity index were calculated for each plan. [24] Doses to critical structures were assessed by their mean dose and D 1%. Conformity Index = (V Target95% /V Tumor ) (V Target95% /V Body95% ) Homogeneity Index = (D5%-D95%)/Mean dose to target Translational shifts after daily registration have been reported in terms of mean, individual patient mean, standard deviation and standard error of mean. Systematic error and population random error have been calculated by following ways. Systematic error (Σ) = Standard deviation of mean shifts per patient. Random error (σ) = Root mean square of standard deviation of each patient. 256 Journal of Cancer Research and Therapeutics - April-June 2013 - Volume 9 - Issue 2

Three-dimensional registration system of helical tomotherapy gives information of translational and rotational shifts of patient compared to planning scan. After correction of setup error, the resultant translational movement from origin has been calculated by dimension of vector. Vector of one fraction of an individual patient = (x 2 +y 2 +z 2 ) Where x is lateral shift, y is vertical and z is caudo-cranial shift. RESULTS Fifty-three patients of prostate carcinoma who were accrued in an IRB-approved prospective protocol, treated with helical tomotherapy-based IMRT have been prospectively evaluated on dosimetric and clinical aspects. Four patients received postoperative radiotherapy. At presentation, median PSA value was 23 ng/ml (range, 1.60 to 100.37). Most of them (44 patients) had high risk disease. All high risk patients received neoadjuvant hormonal therapy prior to radiotherapy and the median duration of neoadjuvant therapy was 3 months and Table 3: PTV and OAR dose indices Volumes Indicies Mean Standard Deviation Target PTV Prostate V95 (%) 99.26 1.24 V99 (%) 96.71 3.03 V105 (%) 11.69 17.03 PTV nodes V95 (%) 99.38 0.34 V99 (%) 96.89 1.24 V105 (%) 10.73 11.15 Organ at risk Bladder Mean 38.52 8.41 D1 (Gy) 74.99 2.20 V40 (%) 38.52 18.09 V50 (%) 22.72 12.60 V65 (%) 7.79 8.43 Rectum Mean 41.72 6.75 D1 (Gy) 75.23 2.47 V40 (%) 41.33 16.85 V50 (%) 26.37 13.31 V65 (%) 8.81 8.86 Bowel D80cc (Gy) 40.24 16.99 D20cc (Gy) 48.20 15.28 D1cc (Gy) 51.58 12.72 Right Femoral Head Mean (Gy) 23.85 6.70 D1 (Gy) 39.44 10.42 Left Femoral Head Mean (Gy) 23.64 6.64 D1 (Gy) 39.43 10.24 has been planned for concomitant and adjuvant therapy for 2-3 years [Table 1]. Dose to primary and pelvic nodes have been enumerated in Table 2 with respective BED and EQD2 with different a/b (1.5, 3, 10) values [Table 2]. Using an optimization target of 100% of the PTV volume to be covered by 95% of the prescription dose, the mean volume covered by the 95% isodose (V 95% ) was 99.26% (SD 1.24) for the PTV primary and 99.38% (SD 0.34) for PTV nodes [Table 3]. Dose to 1% volume of bladder and rectum were 74.99 Gy (SD 2.20) and 75.23 Gy (SD 2.47), respectively. V40, V50 and V65 of bladder were 38.52%, 22.72% and 7.79%, respectively. Similarly in rectum volume received 40%, 50% and 65% of prescribed dose were 41.33, 26.37 and 8.81%, respectively. Mean dose received by 1 cc of bowel was 51.58 Gy (SD 12.72). Right and left femoral head received mean dose of 23.85 Gy (SD 6.70) and 23.64 Gy (SD 6.64), respectively [Table 3]. The required PTV margins for translational movements have been validated by implementing Marcel van Hark s formula in first 500 observations. Required PTV margin (90% probability of CTV volume to be covered by 95% of isodose curve) for lateral, longitudinal and vertical axes were 11.30 mm, 9.95 mm and 13.49 mm, respectively [Table 4]. Resultant vectors of translational shifts were mostly between 3 mm and 15 mm and were distributed normally with 165 observations between 6 and 10 mm [Table 5]. Offline audit of shift data revealed 7% to 8% chance of missing a part of CTV if patients were treated without image guidance with a uniform 10 mm CTV to PTV expansion [Table 6]. All patients except two completed their scheduled radiotherapy treatment. One patient defaulted radiotherapy after receiving 22 Gy (planned for 74 Gy in 37 fractions) and radiotherapy has been prematurely concluded in other patient at 45 Gy (planned for 60 Gy in 20 fractions) due grade 3 genitourinary complication. Most patients have tolerated treatment well with 14 (26.4%) and 12 (22.6%) grade 2 acute rectal and urinary toxicity, respectively [Table 7]. After median follow-up of 23 months for the whole cohort of 53 patients, the biochemical relapse-free survival rate is 95.2% Table 4: Translational and rotational shifts after co-registration (500 consecutive observations in first 21 patients) Lateral (cm) Longitudinal (cm) Vertical (cm) Pitch (degree) Roll (degree) Yaw (degree) Mean 0.88 1.88 2.60 0.02 0.31 0.11 Median 0.25 1.45 1.75 0.00 0.30 0.00 Standard deviation 3.41 3.00 4.06 0.41 0.62 0.49 SEM 0.28 0.26 0.31 0.04 0.06 0.05 Systematic error 0.58 1.39 4.07 0.15 0.29 0.01 Σ (SD of systematic error) 3.41 3.00 4.06 0.41 0.62 0.49 σ (Population random error) 3.96 3.49 4.77 0.72 0.73 0.76 Margin required for non image guidance IMRT 11.30 9.95 13.49 1.53 2.04 1.76 Journal of Cancer Research and Therapeutics - April-June 2013 - Volume 9 - Issue 2 257

Table 5: Vector of translational shifts (500 consecutive observations in first 21 patients) Vector (x 2 +y 2 +z 2 ) in mm Number of observations 0 to 3 mm 39 More than 3 mm up to 6 mm 138 More than 6 mm up to 10 mm 165 More than 10 mm up to 15 mm 108 More than 15 mm up to 20 mm 39 More than 20 mm 11 Table 7: Acute toxicity profiles (RTOG) Organs Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Gastrointestinal 10 29 14 0 0 (18.9%) (54.7%) (26.4%) Genitourinary 10 (18.9%) 30 (56.6%) 12 (22.6%) 1 (2%) 0 (nadir +2 definition). [23] Three-year actuarial biochemical relapse-free survival is 78.4%. At median follow-up, overall survival is 95.0%. DISCUSSION Recently published clinical data suggest a/b ratio of 1.5 Gy for prostate cancer, which is lower than for rectum of 3 to 6 Gy. [12] This would suggest the role of hypofractionated radiotherapy regimens in dose escalation and differentially improving the therapeutic ratio by increasing local control rates at acceptable rectal toxicity. There have been multiple phase three trials testing the above hypothesis against conventional fractionation. The use of higher doses especially >74-80 Gy resulted in better biochemical and local control rates than conventional doses of <70 Gy. Initial dose escalation trials using conventional external beam radiation therapy (EBRT) techniques resulted in unacceptably high rates of morbidity. With conventional techniques, it was not always feasible to safely deliver high doses of radiation to the prostate without exceeding the tolerance of the surrounding bowel and bladder, resulting in serious late toxicity. [10-11] So, it is postulated that hypofractionated dose escalation with the help of IMRT-based planning and treatment delivery under image guidance can bring the required balance in adequate local control rates and low rectal toxicity. One of the recent studies by Pollack et al. compared 70.2 Gy/26# versus 76 Gy/38# using IMRT reported acute toxicity grade 3 or more in 8% versus 2%, respectively. [25] The longterm results showed 23% difference in the freedom from biochemical failure (FFF) with hypofractionation at the median follow-up of 8.7 years. [26] There was no grade 3 or more late toxicity reported. In other trials by Arcangeli et al. and Norkus et al. with 3.1 to 3 Gy per fractions using 3DCRT also reported acute toxicity grade 3 or more in 1% or less, respectively. [27,28] Most of the studies have shown improvement of biochemical Table 6: Chance (%) of missing the target by non image guidance IMRT Directions No Image Guidance 7 mm 10 mm 15 mm Lateral 16.9 7.1 1.9 Longitudinal 13.4 7.7 3 Vertical 19.4 7.7 1.4 control rates with hypofractionated treatments when the equivalent doses were 80 Gy 3 with low acute toxicity rates (grade 3 or more <5%). Maggio et al. reported safe delivery of median dose of 100 Gy (EQD (2, a/b = 10) = 113 Gy) to the dominant intraprostatic lesion (DIL) using hypofractionated RT with IGRT without violating safe constraints for the organs at risk. [29] The typical rectal NTCP values were around or below 1%-3% for G3 toxicity and 5%-7% for G2-G3 toxicity. For the 100 Gy DIL dose boost strategy, mean D95% of DIL and PTVDIL were 98.8 Gy and 86.7 Gy, respectively. In present series no undue toxicity ( grade 3 acute genitourinary or gastrointestinal toxicity) was observed. It has been demonstrated before that the volume of rectum, which receives doses of 20-50 Gy correlates with acute toxicity; this is very well confirmed in the current study also. [29] In a recent CHHip trial which randomly assigned 153 patients to conventional (74 Gy/37#) or hypofractionated high-dose intensity-modulated radio therapy (60 Gy/20# or 57 Gy/19#). At 50 5 months median follow-up (IQR 43 5-61 3), six (4 3%; 95% CI 1 6-9 2) of 138 in conventional group; 5 of 137 (3 6%; 1 2-8 3) in 60 Gy and two of 143 (1 4%; 0 2-5 0) had bowel toxicity of grade 2 at 2 years. For bladder also there was no significant difference in toxicities in various arms. [30] The genitourinary toxicity largely depends on the overlap volume of PTV with bladder mucosa. Unlike previous studies a uniform margin around the CTV as overlapping volumes over bladder and rectum were not given any differential weightage. This means, there was no difference in the dose prescription and constraints applied to the portion of the PTV overlapping the rectum. The low acute toxicity seen in present series suggests that the effect of higher doses in a relatively small overlapping volume, which gets diffused over the treatment course due to variable rectal anatomy. The systematic use of rectal emptying procedures like diet, laxatives, rectal enema/ wash rectal balloons may be used to further reduce the prostate and rectal motion as reported by some investigators. This can further help reduce toxicity. [31-33] To contain acute as well as late toxicity, it is important to achieve maximum sparing of organs at risk while treatment planning and precise treatment delivery using image guidance to obviate set-up errors and internal organ motion. Most of the modern series have used IMRT for treatment planning with 258 Journal of Cancer Research and Therapeutics - April-June 2013 - Volume 9 - Issue 2

various techniques for image guidance like ultrasound, DRR with implanted fiducials, CBCT and MVCT as per availability. [11] Schubert et al. had reported setup errors of 1274 prostate patients treated with helical tomotherapy and found a vector displacement of more than 10 mm in 48.1% of the fractions. [34] In the current series it was proved that in absence of image guidance there is a chance of missing the CTV marginally in 7% to 8% of fractions with 1 cm margins [Table 6]. On analysis of 500 observations, a vector displacement of more than 10 m was seen in 46% of the treatment fractions. The availability of online image gating capability for correction of intrafraction movement would have further helped in reducing the chances of errors although the dosimetric effect of observed prostate motion on target is small and infrequently severe. [35] Like other studies, 96% biochemical response has been achieved at median follow-up of 15 months. [11] The 2-year actuarial biochemical relapse-free survival (80.6%) is also comparable with other series. [11,12] The long-term toxicity and outcomes cannot be reported adequately and would require longer follow-up in larger number of patients. The current work reports feasibility of safe practice of hypofractionated radiation and is found comparable to literature. The tomotherapy-based treatment planning was found to be capable of achieving maximum sparing of organs at risk, without compromising target coverage. The image guidance using MVCT was also satisfactory in daily online matching and set-up correction. So the use of hypofractionated schedules in prostate cancer is justified with minimal acute toxicity and acceptable short-term local control rates when practiced with image guidance. This study is important in the set up of a developing nation because hypofractionated regimens promising more convenient treatment schedules reduces outpatient travel and overall machine commitments in constraint set up. This is the first study from India to systematically report the use of hypofractionated schedules in prostate cancer with acceptable acute toxicity and short-term local control rates when practiced with image guidance. Hypofractionated RT has the potential to reduce the machine burden in a busy department while image guidance largely negates the effect of organ motion and set-up errors, which can have a larger detriment with hypofractionation. REFERENCES 1. Dearnaley DP, Sydes MR, Graham JD, Aird EG, Bottomley D, Cowan RA, et al. Escalated-dose versus standard- dose conformal radiotherapy in prostate cancer: First results from the MRC RT01 randomised controlled trial. Lancet Oncol 2007;8:475-87. 2. Hanks GE, Hanlon AL, Epstein B, Horwitz EM. Dose response in prostate cancer with 8-12 years follow-up. Int J Radiat Oncol Biol Phys 2002;54:427-35. 3. Peeters ST, Heemsbergen WD, Koper PC, van Putten WL, Slot A, Dielwart MF, et al. Dose-response in radiotherapy for localized prostate cancer: Results of the Dutch multicenter randomized Phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol 2006;24:1990-6. 4. Pollack A, Zagars GK, Smith LG, Lee JJ, von Eschenbach AC, Antolak JA, et al. Preliminary results of a randomized radiotherapy doseescalation study comparing 70 Gy with 78 Gy for prostate cancer. J Clin Oncol 2000;18:3904-11. 5. Zietman AL, DeSilvio ML, Slater JD, Lee JJ, von Eschenbach AC, Antolak JA, et al. Comparison of conventional dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: A randomized controlled trial. JAMA 2005;294:1233-9. 6. Zelefsky MJ, Fuks Z, Hunt M, Yamada Y, Marion C, Ling CC, et al. Highdose intensity modulated radiation therapy for prostate cancer: Early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys 2002;53:1111-6. 7. Jani AB, Su A, Correa D, Gratzle J. Comparison of late gastrointestinal and genitourinary toxicity of prostate cancer patients undergoing intensity modulated versus conventional radiotherapy using localized fields. Prostate Cancer Prostatic Dis 2006;10:82-6. 8. De Meerleer GO, Fonteyne VH, Vakaet L, Villeirs GM, Denoyette L, Verbaeys A, et al. Intensity-modulated radiation therapy for prostate cancer: Late morbidity and results on biochemical control. Radiother Oncol 2007;82:160-6. 9. Chism DB, Horwitz EM, Hanlon AL, Pinover WH, Mitra RK, Hanks GE. Late morbidity profiles in prostate cancer patients treated to 79-84 Gy by a simple four-field coplanar beam arrangement. Int J Radiat Oncol Biol Phys 2003;55:71-7. 10. Smit WG, Helle PA, van Putten WL, Pinover WH, Mitra RK, Hanks GE. Late radiation damage in prostate cancer patients treated by high dose external radiotherapy in relation to rectal dose. Int J Radiat Oncol Biol Phys 1990;18:23-9. 11. Cahlon O, Hunt M, Zelefsky MJ. Intensity-modulated radiation therapy: Supportive data for prostate cancer. Semin Radiat Oncol 2008;18:48-57. 12. Miles EF, Lee WR. Hypofractionation for prostate cancer: A critical review. Semin Radiat Oncol 2008;18:41-7. 13. Langen KM, Jones DT. Organ motion and its management. Int J Radiat Oncol Biol Phys 2001;50:265-78. 14. Balter JM, Sandler HM, Lam K, Bree RL, Lichter AS, ten Haken RK. Measurement of prostate movement over the course of routine radiotherapy using implanted markers. Int J Radiat Oncol Biol Phys 1995;31:113-8. 15. Vigneault E, Pouliot J, Laverdière J, Roy J, Dorion M. Electronic portal imaging device detection of radio opaque markers for the evaluation of prostate position during megavoltage irradiationa clinical study. Int J Radiat Oncol Biol Phys 1997;37:205-12. 16. Lattanzi J, McNeeley S, Hanlon A, Das I, Schultheiss TE, Hanks GE. Daily CT Localization for correcting portal errors in the treatment of prostate cancer. Int J Radiat Oncol Biol Phys 1998;41:1079-86. 17. D Amico AV, Whittington R, Malkowicz RB, Schultz D, Blank K, Broderick G, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969-74. 18. Murthy V, Shukla P, Adurkar P, Master Z, Mahantshetty U, Shrivastava SK. Dose variation during hypofractionated image-guided radiotherapy for prostate cancer: Planned versus delivered. J Cancer Res Ther 2011;7:162-7. 19. Boehmer D, Maingon P, Poortmans P, Baron MH, Miralbell R, Remouchamps V, et al. Guidelines for primary radiotherapy of patients with prostate cancer. Radiother Oncol 2006;79:259-69. 20. Lawton CA, Michalski J, El-Naqa I, Buyyounouski MK, Lee WR, Menard C, et al. RTOG GU Radiation oncology specialists reach consensus on pelvic lymph node volumes for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2009;74:383-7. Journal of Cancer Research and Therapeutics - April-June 2013 - Volume 9 - Issue 2 259

21. Langen KM, Papanikolaou N, Balog J, Crilly R, Followill D, Goddu SM, et al. QA for helical tomotherapy: Report of the AAPM Task Group 148. Med Phys 2010;37:4817-53. 22. Fiorino C, Sanguineti G, Cozzarini C, Fellin G, Foppiano F, Menegotti L, et al. Rectal dose-volume constraints in high-dose radiotherapy of localized prostate cancer. Int J Radiat Oncol Biol Phys 2003;57:953-62. 23. Roach M 3rd, Hanks G, Thames H Jr, Schellhammer P, Shipley WU, Sokol GH, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006;65:965-74. 24. Paddick I. A simple scoring ratio to index the conformity of radiosurgical treatment plans. Technical note. J Neurosurg 2000;93:219-22. 25. Pollack A, Hanlon A, Horwitz EM, Feigenberg SJ, Konski AA, Movsas B, et al. Dosimetry and preliminary acute toxicity in the ûosi 100 men treated for prostate cancer on a randomized hypofractionation dose escalation trial. Int J Radiat Oncol Biol Phys 2006;64:518-26. 26. Pollack A, Walker G, Buyyounouski M, Feigenberg SJ, Konski AA, Movsas B, et al. Five year results of a randomized external beam radiotherapy hypofractionation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2011;81:S1. 27. Arcangeli G, Fowler J, Gomellini S, Arcangeli S, Saracino B, Petrongari MG, et al. Acute and late toxicity in a randomized trial of conventional versus hypofractionated three-dimensional conformal radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2011;79:1013-21. 28. Norkus D, Miller A, Kurtinaitis J, Haverkamp U, Popov S, Prott FJ, et al. A randomized trial comparing hypofractionated and conventionally fractionated three-dimensional external beam radiotherapy for localized prostate adenocarcinoma a report on acute toxicity. Strahlenther Onkol 2009;185:715-21. 29. Maggio A, Fiorino C, Mangili P, Cozzarini C, de Cobelli F, Cattaneo GM, et al. Feasibility of safe ultra-high (EQD(2)>100 Gy) dose escalation on dominant intra-prostatic lesions (DILs) by Helical Tomotheraphy. Acta Oncol 2011;50:25-34. 30. Dearnaley D, Syndikus I, Sumo G, Bidmead M, Bloomfield D, Clark C, et al. Conventional versus hypofractionated high-dose intensitymodulated radiotherapy for prostate cancer: Preliminary safety results from the CHHiP randomised control trial. Lancet Oncol 2012;13:43-54. 31. Patel RR, Orton N, Tome WA, Chappell R, Ritter MA. Rectal dose sparing with a balloon catheter and ultrasound locali-zation in conformal radiation therapy for prostate cancer. Radiother Oncol 2003;67:285-94. 32. Teh BS, Dong L, McGary JE, Mai WY, Grant W 3rd, Butler EB. Rectal wall sparing by dosimetric effect of rectal balloon used during intensity-modulated radiation therapy (IMRT) for prostate cancer. Med Dosim 2005;30:25-30. 33. Teh BS, McGary JE, Dong L, Mai WY, Carpenter LS, Lu HH, et al. The use of rectal balloon during the delivery of intensity modulated radiotherapy (IMRT) for prostate cancer: More than just a prostate gland immobilization device? Cancer J 2002;8:476-83. 34. Schubert LK, Westerly DC, Tomé WA, Mehta MP, Soisson ET, Mackie TR, et al. A comprehensive assessment by tumor site of patient setup using daily MVCT imaging from more than 3,800 helical tomotherapy treatments. Int J Radiat Oncol Biol Phys 2009;73:1260-9. 35. Langen KM, Lu W, Willoughby TR, Chauhan B, Meeks SL, Kupelian PA, et al. Dosimetric effect of prostate motion during helical tomotherapy. Int J Radiat Oncol Biol Phys 2009;74:1134-42. Cite this article as: Murthy V, Krishnatry R, Mallik S, Master Z, Mahantshetty U, Shrivastava S. Helical tomotherapy-based hypofractionated radiotherapy for prostate cancer: A report on the procedure, dosimetry and preliminary clinical outcome. J Can Res Ther 2013;9:253-60. Source of Support: Nil, Conflict of Interest: Nil. 260 Journal of Cancer Research and Therapeutics - April-June 2013 - Volume 9 - Issue 2