Assessment of normal tissue complications following prostate cancer irradiation: Comparison of radiation treatment modalities using NTCP models Rungdham Takam and Eva Bezaka兲 School of Chemistry and Physics, The University of Adelaide, Adelaide SA 5000, Australia and Department of Medical Physics, Royal Adelaide Hospital, Adelaide SA 5000, Australia Eric E. Yeoh School of Medicine, The University of Adelaide, Adelaide SA 5000, Australia and Department of Radiation Oncology, Royal Adelaide Hospital, Adelaide SA 5000, Australia Loredana Marcu School of Chemistry and Physics, The University of Adelaide, Adelaide SA 5000, Australia and Faculty of Science, University of Oradea, Oradea 410086, Romania 共Received 13 August 2009; revised 20 July 2010; accepted for publication 21 July 2010; published 31 August 2010兲 Purpose: Normal tissue complication probability 共NTCP兲 of the rectum, bladder, urethra, and femoral heads following several techniques for radiation treatment of prostate cancer were evaluated applying the relative seriality and Lyman models. Methods: Model parameters from literature were used in this evaluation. The treatment techniques included external 共standard fractionated, hypofractionated, and dose-escalated兲 three-dimensional conformal radiotherapy 共3D-CRT兲, low-dose-rate 共LDR兲 brachytherapy 共I-125 seeds兲, and highdose-rate 共HDR兲 brachytherapy 共Ir-192 source兲. Dose-volume histograms 共DVHs兲 of the rectum, bladder, and urethra retrieved from corresponding treatment planning systems were converted to biological effective dose-based and equivalent dose-based DVHs, respectively, in order to account for differences in radiation treatment modality and fractionation schedule. Results: Results indicated that with hypofractionated 3D-CRT 共20 fractions of 2.75 Gy/fraction delivered five times/week to total dose of 55 Gy兲, NTCP of the rectum, bladder, and urethra were less than those for standard fractionated 3D-CRT using a four-field technique 共32 fractions of 2 Gy/fraction delivered five times/week to total dose of 64 Gy兲 and dose-escalated 3D-CRT. Rectal and bladder NTCPs 共5.2% and 6.6%, respectively兲 following the dose-escalated four-field 3D-CRT 共2 Gy/fraction to total dose of 74 Gy兲 were the highest among analyzed treatment techniques. The average NTCP for the rectum and urethra were 0.6% and 24.7% for LDR-BT and 0.5% and 11.2% for HDR-BT. Conclusions: Although brachytherapy techniques resulted in delivering larger equivalent doses to normal tissues, the corresponding NTCPs were lower than those of external beam techniques other than the urethra because of much smaller volumes irradiated to higher doses. Among analyzed normal tissues, the femoral heads were found to have the lowest probability of complications as most of their volume was irradiated to lower equivalent doses compared to other tissues. © 2010 American Association of Physicists in Medicine. 关DOI: 10.1118/1.3481514兴 Key words: NTCP models, prostate radiotherapy I. INTRODUCTION The main therapeutic aim of all radiotherapy treatment techniques including those for prostate cancer is to maximize damage to the tumor while, at the same time, keeping damage to the surrounding normal tissues as small as possible. During treatment planning, normal tissue complication probability 共NTCP兲 as well as tumor control probability 共TCP兲 should be assessed, so as to optimize the therapeutic ratio of any particular radiotherapy modality. Among plans which have similar TCP, the one with the lowest NTCP should be considered superior. Many groups have published tumor control results following various radiotherapy techniques 共external beam and 5126 Med. Phys. 37 „9…, September 2010 brachytherapy兲 based on biochemical and other clinical outcomes. For instance, Livsey et al.1 reported 5 yr overall survival and disease-specific survival rate in patients with prostate cancer who received hypofractionated 共3.13 Gy/fraction兲 four-field conformal radiotherapy of 83.1% and 91%, respectively. Kupelian et al.2 analyzed the long term relapse-free survival rates in the patients treated with hypofractionated 共2.5 Gy/fraction for 70 Gy兲 radiotherapy using the intensity modulated radiation therapy technique and observed 5 yr overall American Society for Therapeutic Radiology and Oncology biochemical relapse-free survival and Houston 共nadir+ 2兲 biochemical relapse-free survival rates of 85% and 88%, respectively. 0094-2405/2010/37„9…/5126/12/$30.00 © 2010 Am. Assoc. Phys. Med. 5126 5127 Takam et al.: Normal tissue complications following prostate cancer irradiation Blasko et al.3 reported the 9 yr overall biochemical control rate of 83.5% in a group of patients treated with lowdose-rate brachytherapy 共LDR-BT兲 using palladium-103 共Pd-103兲 for a minimum dose of 115 Gy. Twelve-year overall and disease-specific survival rates of 84% and 93%, respectively, were observed among patients treated with LDR-BT using I-125 or Pd-103.4 Similarly, Zelefsky et al.5 reported the 8 yr nadir+ 2 prostate specific antigen-disease-free survival 共PSA-DFS兲 rates of 73%, 60%, and 41% for low, intermediate, and high-risk prostate cancer patients, respectively, treated with I-125 LDR-BT 共median dose of 160 Gy兲. In addition, for those patients who received Pd-103 LDR-BT 共median dose of 120 Gy兲, the 8 yr nadir+ 2 PSA-DFS rates for low, intermediate, and high-risk patients were 73%, 64%, and 38%, respectively. Poor implant quality as reflected by D90 value 共the dose received by 90% of target volume兲 may have contributed to slightly lower tumor control rates in this study compared with previous reports.3,4 Mark et al.6 investigated the treatment outcomes of Ir-192 high-dose-rate brachytherapy 共HDR-BT兲 共45 Gy in six fractions兲 in localized prostate cancer patients and found that the PSA disease-free survival rate was 90.3%. For a comprehensive list of studies, see the review by Nilsson et al.7 For the treatment of prostate cancer, while TCP increases with increasing dose, the total radiation dose which can be given to the prostate is limited by the tolerance of surrounding normal tissues such as the bladder, rectum, urethra, and bowel. As shown above, although differences in dose levels, fractionation, and quality of treatment delivery can affect the efficacy of radiation treatment, clinical studies indicate that currently used treatment techniques generally report similar tumor control.7 As a result, assessment of NTCP values for organs-at-risk 共OARs兲 in association with each treatment plan or technique would assist clinicians and patients in the selection of suitable treatment modality and dose per fraction for a given treatment. The purpose of the current study is to assess NTCP of the rectum, bladder, urethra, and femoral heads, following radiation treatment of prostate carcinoma using the relative seriality and Lyman models. Real patient plans for external beam radiotherapy 共EBRT兲, LDR, and HDR brachytherapy techniques, which had evolved approximately over a 7 yr period at our center, were evaluated. Currently, EBRT and LDR brachytherapy are used as monotherapy but HDR is combined with EBRT. II. MATERIALS AND METHODS II.A. Prostate treatment techniques and differential dose-volume histograms Contouring of normal tissues in all plans was carried out by one radiation oncologist only to ensure that all organs were contoured consistently for all patients and treatment techniques analyzed. While this does not eliminate intraobserver variability in contouring, this variability is minimized by using absolute rather than percent volumes of the contoured OARs in the dose-volume histograms 共DVHs兲.8 The full extent of the rectum and bladder were contoured based Medical Physics, Vol. 37, No. 9, September 2010 5127 on CT slices of the entire pelvis obtained at 2–3 mm intervals in the axial plane. The rectum was defined as extending from the anal canal to the rectosigmoid junction. Intravenous contrast was used to assist in the definition of the bladder for contouring purposes. The urethra was not contoured for the EBRT techniques as this normal tissue would have received the same homogenous radiation dose as the prostate. Following the dose calculation, DVHs of the rectum, bladder, and urethra were exported from the corresponding treatment planning systems. In total, 215 DVHs from 101 patients were analyzed in this study. Real treatment plans of treated patients were used in the current study. As a result, different groups of patients are compared when analyzing individual radiotherapy techniques. While acknowledging that this introduces another variable into the study, it allows our risk estimates to be correlated with patient data in the future. Details about each treatment technique are briefly described in Table I. While the heterogeneity of the techniques is acknowledged, this has resulted from the development and validation of treatment techniques reported in the medical literature. For example, HDR-BT is now acknowledged to have an emerging role in the management of prostate cancer.9 Although HDR-BT as monotherapy is currently not yet available at our center, the promising results in terms of treatment efficacy and low normal tissue toxicities of HDR-BT as monotherapy 共often prescribed as four fractions of 9.5 Gy兲 for prostate cancer have been recently reported.10–16 In order to simulate the effect on NTCP using HDR-BT as monotherapy, the original HDR-BT live treatment plans used for the combined modality treatment were used as monotherapy plans by increasing the number of fractions 共of 9.5 Gy兲 from two to four 共same dose distribution was assumed for each fraction兲. II.B. Biologically effective dose and equivalent dose conversion techniques The probabilities of normal tissue complications were calculated from differential DVHs of organs-at-risk. The physical dose-based differential DVHs from hypofractionated three-dimensional conformal radiotherapy 共3D-CRT兲, HDR-BT 共live planning兲, and LDR-BT 共live planning兲 were first converted to biologically effective dose 共BEffD兲-based differential DVHs 共BEffDVHs兲 in order to normalize the doses in the DVHs to the same biological end-point. This conversion was performed using the formalism developed by Dale17 BEffD = DⴱRE, 共1兲 where D is the delivered physical dose 共Gy兲 and RE is a function of dose called relative effectiveness as defined in Eqs. 共2兲–共4兲 in the following sections. II.B.1. Dose conversion for hypofractionated 3DCRT, HDR-BT, and LDR-BT Relative effectiveness for hypofractionated 3D-CRT with dose per fraction d can be written as17 Same as 共1兲 Nucletron SPOT-PRO™ 共live planning兲 Nucletron SWIFT™ 共live planning兲 The prostate gland with a 275.0⫾ 24.5 共249.1–314.6兲 1.5 cm 95% isodose margina Same as 共1兲 297.9⫾ 55.6 共253.6–429.2兲 Same as 共1兲 198.0⫾ 55.7 共112.9–283.8兲 Same as 共1兲 for the first 64 Gy, then prostate gland with no margin 201.3⫾ 85.7 共93.0–396.9兲 d , 共␣/␤兲 共2兲 冋 冉 冊册 2R0␭ ␤ ␮−␭ ␣ ⴱ 关1 − e−共␭T兲兴−1 ⴱ 冎 1 关1 − e−T共␮+␭兲兴 , ␮+␭ 再 1 关1 − e−共2␭T兲兴 2␭ 共3兲 N/A 冉冊 R0 ␤ , ␮+␭ ␣ 共4兲 9.5 Nucletron MicroSelectron HDR where, R0 is the initial dose rate 共0.0704 Gy/h兲, ␭ is the source decay constant 共0.000 48 h−1兲, and ␮ is the rate of sublethal damage repair.18 Following the BEffD conversion of DVHs, in order to account for the differences in dose fractionation schemes such as between standard fractionated 共2 Gy/fraction for 64 Gy兲 and hypofractionated 共2.75 Gy/fraction for 55 Gy兲, and also between HDR-BT and LDR-BT, BEffDVHs were subsequently converted to equivalent dose 共Deq兲-based differential DVHs 共DeqVHs兲. Equivalent dose Deq for a particular dose delivering scheme is the dose which would be given using conventionally fractionated 共2 Gy/fraction兲 irradiation for the same biological effect. It can be calculated using the formalism developed by Nag and Gupta19 Deq = Reference 8. 38 7 cGy h−1 145 2 70 RE = 1 + a N/A where R0 is the initial dose rate 共⬃94.86 Gy/ h兲, ␭ is the source decay constant 共0.000 39 h−1兲, ␮ is the rate of sublethal damage repair 共0.46 h−1兲,18 and T is the total treatment time 共⬃25 min per fraction兲. For a permanent implant with a 共infinite兲 decaying source as used in LDR-BT, assuming that repair rates never exceed rates of double-strand break induction and without cell proliferation, the relative effectiveness in this case is defined as17 共6兲 HDR-BT monotherapy 共Ir-192兲 共n = 19兲 共2兲 Hypofractionated 3D-CRT 共n = 30兲 共3兲 Dose-escalated 3D-CRT 共n = 44兲 共4兲 Five-field 3D-CRT 共n = 42兲 5128 where ␣ / ␤ is the dose when the linear and quadratic components of cell killing are equal 共using the linear-quadratic dose-response model兲. Relative effectiveness for a nonpermanent implant with a decaying radioactive source as used in HDR-BT is defined as17 − 共5兲 LDR-BT monotherapy 共I-125兲 共n = 73兲 2 2.75 2 64 55 70 or 74 共1兲 Standard fractionated 3D-CRT 共n = 21兲 RE = 1 + RE = 1 + 18 MV photons 共Varian 2100EX兲, four-field 共AP/PA, laterals兲 Same as 共1兲 Same as 共1兲 18 MV photons 共Varian 2100EX兲, five-field 共AP/two laterals, two obliques兲 Average needles used: 24; average seeds implanted: 70 Margin Average planning treatment volume 共PTV兲 in cm3 共range兲 Beams arrangement or implantation Dose/fraction Prescription or dose rate 共Gy兲 dose 共Gy兲 Treatment technique 共n = no. of DVH兲 TABLE I. Radiation treatment techniques for prostate carcinoma at Royal Adelaide Hospital, Radiation Oncology Department, South Australia, which were involved in this study. Pinnacle3 6.2b 共Phillips Medical System兲 Same as 共1兲 Same as 共1兲 Takam et al.: Normal tissue complications following prostate cancer irradiation Treatment planning system 5128 Medical Physics, Vol. 37, No. 9, September 2010 BEffD , 共1 + dref/␣/␤兲 共5兲 where dref is the reference dose per fraction for a conventionally fractionated EBRT. In this study, the dref was 2 Gy/ fraction. The aim of conversion of physical doses in DVHs to BEffD and Deq in this study was to normalize the physical dose from individual radiation treatment techniques to the dose which would produce the same biological end-point 共BEffD兲 as that of the standard fractionated 共2 Gy/fraction兲 dose schedule 共Deq兲. For standard fractionated 3D-CRT or other EBRT techniques based on 2 Gy fraction delivering scheme, these dose conversions were not needed because the final Deq obtained from BEffD conversions will be equal to the original physical 5129 Takam et al.: Normal tissue complications following prostate cancer irradiation 5129 TABLE II. The default parameter values of the relative seriality and the Lyman models for organs-at-risk involved in this study. Default values Parameters 共1兲 共2兲 共3兲 共4兲 共5兲 ␣ / ␤ ratio s k m n Rectum Bladder a a 5.4 Gy 0.75c 10.64e – – 7.5 Gy 1.3d 14.5e – – 80 Gy for symptomatic bladder contracture and volume lossb 80 Gy for severe proctitis/necrosis/ stenosis/fistulab 共6兲 D50 Urethra Femoral heads 7.5 Gy关estimated兴 1.0关estimated兴 14.5e – – 6 Gyb – – 0.12b 0.25b 68 Gy for clinical stricture/ perforationb 65 Gy for Necrosisb a Reference 25. Reference 26. c Reference 24. d Reference 27. e Reference 28. b doses. The original differential DVHs obtained from treatment planning system were used directly in these cases. II.C. NTCP calculations The relative seriality model was applied to most of the DeqVHs in this study, with the model parameters of the organs of interest for specified end points obtained from literature. This model was chosen mainly because it accounts for the architecture of the organ through parameter “s,” which is derived from the ratio of serial subunits to all subunits in the organ.20 In this scheme, an organ where the substructures are organized in series becomes nonfunctional when one substructure is damaged, while for a parallel organ, the probability of complication depends on the fraction of substructures damaged.21 Hence, the magnitude of volume irradiated to a certain radiation dose will strongly affect the final outcome of irradiated normal organ. This is particularly important for brachytherapy techniques where small volumes are exposed to high doses. The following logistic function was used to estimate the NTCP:22–24 再 冋 冉 NTCP = 1 − 兿 1 − i 1 1 + 共D50/Deq,i兲k 冊册 s ␯i/V 冎 1/s . 共6兲 D50 in the above equation represents the dose required to produce 50% probability of specific tissue complications, ␯i is the normal organ subvolume which received the equivalent dose Deq,i. Parameters s and “k” are empirically determined NTCP parameters which dictate the seriality of the organ structural architecture and steepness of dose-response curve, respectively. Model parameters used for calculations of NTCP for each OAR are summarized in Table II. The model parameters for calculation of the NTCP of the urethra are not readily available despite extensive reports of urethral toxicity following various prostate cancer radiotherapy techniques. For example, Burman et al.26 lists sevMedical Physics, Vol. 37, No. 9, September 2010 eral OARs end points and tolerance parameters for use in estimating NTCP following radiotherapy but not the urethra. As the urethra has similar anatomical structures to OARs such as the colon, esophagus, and small intestine, and strictures leading to the obstruction of the passage of the luminal contents are common end points following radiotherapy, it was decided to use the end points and tolerance parameters of the esophagus 共Table II兲 to estimate the urethral NTCP in this work. In addition, in case of standard fractionated and hypofractionated 3D-CRT techniques, the urethra was not contoured and, as a result, differential DVHs of urethra for these techniques were not available. However, assuming that equivalent doses, Deq,i are the same as the target dose and were uniformly delivered to the urethral volume within the prostate, urethral NTCP was calculated using the following equation:23 NTCP = 1 1 + 共D50/Deq,i兲k 共7兲 , where D50 and k have the same definition as described previously. In case of femoral heads, the relative seriality model parameters were not available. Therefore, the Lyman NTCP model with effective volume DVH reduction scheme29–31 was used instead. The Lyman NTCP model may be defined as follows: NTCP共D,V兲 = 1 冑2␲ 冕 t e−共t⬘ 2/2兲 dt⬘ , 共8兲 ⬁ where t= Dmax − D50共␯eff兲 . mⴱD50共␯eff兲 共9兲 The normal deviate t represents the number of standard deviations the point 共Dmax , ␯eff兲 is away from D50共␯eff兲, the 50% tolerance dose for the effective volume 共␯eff兲. D50共␯eff兲 is taken to vary with ␯eff as32 5130 Takam et al.: Normal tissue complications following prostate cancer irradiation D50共␯eff兲 = D50共1兲/共␯eff兲n . 5130 共10兲 The effective volume 共␯eff兲 is calculated using the following equation: ␯eff = 冉 冊 1 D 兺 ␯i Dmaxi ␯ref i 1/n , 共11兲 where ␯ref can be either a volume of the whole organ or reference volume of that organ and n is the volume dependence of the complication probability.26 Model parameters used for femoral heads are shown in Table II. II.D. Assessment of NTCP values dependence on the relative seriality model parameters It is clear from Eq. 共6兲 described above that the relative seriality NTCP model contains several variable parameters such as Deq,i, s, and k. The dose Deq,i 共derived in this study by first converting physical dose to BEffD and then to Deq as described earlier兲 depends on the ␣ / ␤ ratio of the OAR. To investigate the sensitivity of the NTCP values obtained depending on the model parameters, values of ␣ / ␤ ratio, as well as s and k parameters were varied and rectal NTCPs for hypofractionated 3D-CRT and HDR-BT treatment plans were calculated. The parameter k was calculated applying the following equation: k= 4 冑2␲m , 共12兲 showing that it is related to the value of parameter “m” 共the slope of the complication probability vs dose curve兲. Hence, testing of sensitivity on the NTCP model associated with the parameter k can be done either by varying the value of parameter k directly or by varying the value of parameter m. The latter approach was used in this study by varying the value of one parameter at a time while keeping others constant by using their default value. Typical rectal BEffDVHs FIG. 1. A plot shows differential DVHs of rectum obtained from a four-field hypofractionated 3D-CRT treatment plan for prostate. Differential volume 共cm3兲 of rectum was plotted against original physical doses and corresponding converted biological effective doses and equivalent doses. Medical Physics, Vol. 37, No. 9, September 2010 FIG. 2. A plot shows differential DVHs of rectum obtained from a HDR-BT as monotherapy treatment plan for prostate. for the various treatment modalities were used to demonstrate the results of this sensitivity testing in the following subsections. III. RESULTS III.A. DVHs of organs-at-risk Changes in OAR DVHs as a result of physical doses conversion are demonstrated in Figs. 1–3, showing examples of typical differential DVHs of the rectum obtained from fourfield hypofractionated 3D-CRT, HDR-BT, and LDR-BT as monotherapy treatment plans for the prostate. In these figures, the normalized cumulative volume 共%兲 of rectum was plotted against the original physical doses. Calculated NTCP values were statistically analyzed using one-way ANOVA and t-tests for their significance. NTCP for standard four-field 3D-CRT technique and 64 Gy total dose was used as reference. FIG. 3. A plot shows differential DVHs of rectum obtained from a LDR-BT as monotherapy treatment plan for prostate. 5131 Takam et al.: Normal tissue complications following prostate cancer irradiation 5131 TABLE III. Average calculated rectal NTCP following various prostate cancer treatment techniques calculated with relative seriality model and dosimetric parameters 共equivalent dose was used in calculation兲. No. of DVH/patient Average of mean equivalent dose in Gy⫾ S.D 共range兲 Average irradiated volume in cm3 ⫾ S.D 共range兲 Average NTCP in % ⫾ S.D 共range兲 P-value t-value Statistical significance 7 48.5⫾ 4.1 共41.6–53.6兲 93.9⫾ 44.4 共54.6–186.6兲 2.8⫾ 1.0 共1.1–4.1兲 Reference 10 43.9⫾ 2.0 共39.6–46.2兲 83.8⫾ 29.6 共45.9–142.5兲 1.3⫾ 0.2 共1.1–1.6兲 ⬍0.0001 31.32 Yes Dose-escalated 3D-CRT A. Total dose of 70 Gy 13 46.6⫾ 5.5 共38.1–55.8兲 72.0⫾ 31.1 共25.3–141.7兲 3.3⫾ 1.6 共1.2–5.5兲 B. Total dose of 74 Gy 3 51.6⫾ 0.6 共50.8–52.0兲 62.7⫾ 9.8 共51.8–70.9兲 5.2⫾ 1.0 共4.1–6.1兲 Five-field 3D-CRT 共70 Gy at 2 Gy/fraction兲 14 38.6⫾ 5.7 共30.2–51.6兲 98.5⫾ 51.9 共36.6–204.5兲 2.7⫾ 0.9 共1.3–4.1兲 HDR-BT 共Ir-192兲 monotherapy 共4 ⫻ 9.5 Gy兲 9 59.8⫾ 8.3 共49.6–78.5兲 5.4⫾ 2.6 共2.1–8.1兲 0.5⫾ 0.4 共0.0–1.1兲 LDR-BT 共I-125兲 37 61.9⫾ 5.8 共50.5–73.3兲 3.4⫾ 1.0 共1.5–5.3兲 0.6⫾ 0.4 共0.0–1.8兲 0.2637 1.173 No 0.0553 4.072 No 0.5632 0.5932 No ⬍0.0001 17.55 Yes ⬍0.0001 29.27 Yes Treatment technique Standard fractionated 3D-CRT 共64 Gy at 2 Gy/fraction兲 Hypofractionated 3D-CRT 共55 Gy at 2.75 Gy/fraction兲 III.B. NTCP of OARs III.B.1. Rectal NTCP Table III shows the volumetric, radiation dosimetric data, and NTCP of rectum for prostate radiation treatment techniques investigated. Calculations based on the relative seriality model indicate that the risk of rectal complications was the highest following dose-escalated 3D-CRT to a total dose of 74 Gy being approximately 5.2⫾ 1.0%. Average rectal NTCP were smaller for HDR-BT 共0.5⫾ 0.4%兲 and LDR-BT 共0.6⫾ 0.4%兲 treatment plans. The combination of large irradiated volume and high radiation dose exposure led to higher probability of rectal complications in standard fractionated and dose-escalated 3DCRT compared to other techniques. The NTCP in four-field 3D-CRT increases with the increasing total dose and dose escalation can only be recommended if PTV margin can be reduced. With five-field 3D-CRT, radiation beams were arranged in such a way that irradiation of critical organs such as rectum and bladder was minimized. Therefore, the average rectal NTCP following five-field 3D-CRT was smaller than that of dose-escalated four-field 3D-CRT with the same total dose. For HDR-BT and LDR-BT monotherapy, only approximately 1% and 0.1% of rectal tissues were exposed to the prescribed doses, hence, calculated probabilities of rectal complications for these techniques were the lowest. These techniques offer better dose conformality and less peripheral Medical Physics, Vol. 37, No. 9, September 2010 radiation dose exposure of surrounding normal tissues. The lower NTCP values for LDR and HDR brachytherapy were found to be statistically significant. III.B.2. Bladder NTCP Table IV shows the volumetric, radiation dosimetric data, and NTCP of the bladder for various prostate radiation treatment techniques. Similar to rectal complications, it was observed that severe bladder complications are most likely following dose-escalated four-field 3D-CRT 共to a total dose of 74 Gy兲 for prostate cancer. Average bladder NTCP following this technique was 6.6% 共range 5.8%–7.4%兲. Following the same technique with a smaller total dose of 70 Gy delivered to the prostate, the average bladder NTCP was reduced to 5.0% despite a larger irradiated volume. For standard fractionated four-field 3D-CRT, the maximum bladder irradiated volume receiving equivalent dose around 63 Gy was approximately 10%, resulting in an average 1.9% NTCP for bladder. Similar fractions of bladder 共9%兲 were irradiated to lower equivalent dose of 59 Gy from hypofractionated 3D-CRT which led to smaller average bladder NTCP at 0.7%. Similar to the discussion for rectal DVHs analysis, bladder NTCP for hypofractionated four-field 3D-CRT technique resulted in lesser equivalent dose given and smaller volume of bladder irradiated, thus the probability of severe bladder complications was able to be reduced. 5132 Takam et al.: Normal tissue complications following prostate cancer irradiation 5132 TABLE IV. Average calculated bladder NTCP following various prostate cancer treatment techniques calculated with relative seriality model and dosimetric parameters 共equivalent dose was used in calculation兲. Treatment technique Standard fractionated 3D-CRT 共64 Gy at 2 Gy/fraction兲 No. of DVH/patient Average of mean equivalent dose in Gy⫾ S.D 共range兲 Average irradiated volume in cm3 ⫾ S.D 共range兲 Average NTCP in % ⫾ S.D 共range兲 P-value t-value Statistical significance 7 53.4⫾ 4.1 共44.6–56.4兲 133.4⫾ 32.9 共90.7–181.0兲 1.9⫾ 0.2 共1.6–2.3兲 Reference Hypofractionated 3D-CRT 共55 Gy at 2.75 Gy/fraction兲 10 50.8⫾ 4.3 共42.8–54.9兲 119.6⫾ 42.3 共56.0–184.6兲 0.7⫾ 0.2 共0.4–0.9兲 Five-field 3D-CRT 共70 Gy at 2 Gy/fraction兲 14 43.0⫾ 12.2 共20.4–63.7兲 162.4⫾ 99.2 共46.6–456.8兲 3.3⫾ 1.0 共1.4–4.8兲 Dose-escalated 3D-CRT A. Total dose of 70 Gy 13 48.3⫾ 13.3 共20.6–65.5兲 161.7⫾ 72.6 共81.5–306.0兲 5.0⫾ 2.4 共1.3–9.1兲 B. Total dose of 74 Gy 3 44.2⫾ 6.3 共37.9–50.5兲 199.4⫾ 147.9 共72.4–361.8兲 6.6⫾ 0.8 共5.8–7.4兲 III.B.3. Urethral NTCP ⬍0.0001 23.24 Yes 0.0002 5.146 Yes ⬍0.0001 5.784 Yes 0.0095 10.18 Yes Table V shows the volumetric, radiation dosimetric data, and NTCP of urethra for radiation treatment techniques discussed. As expected, urethral NTCPs following standard fractionated and hypofractionated four-field 3D-CRT techniques were higher than those for other organs due to uniform high-dose exposure. Following standard fractionated 3D-CRT, average urethral NTCP was found to be approximately 9% 共range 8.2%–11.2%兲. Similar high average urethral NTCP was also predicted for HDR-BT 共18.4%, range 12.2%–31.1%兲 as well as LDR-BT 共24.7%, range 12.0%– 55.1%兲. The corresponding average urethral NTCP for hypofractionated four-field 3D-CRT was lower at 3.6%. are shown in Table VI. Necrosis of femoral heads may be a consequence of excessive exposure to radiation from prostate radiotherapy. Assessment of femoral heads DVHs retrieved from treatment plans for dose-escalated four-field 3D-CRT treatment for prostate cancer indicated that approximately 11% and 14% of the femoral heads volume was irradiated to doses of 70 and 74 Gy, respectively. The mean equivalent dose received was lower than other OARs partly because of their distance from the treated volume. Accordingly, an average NTCP for femoral heads was observed to be as low as 0.02% for dose-escalated four-field 3D-CRT 共to total dose of 70 Gy兲 and 0.06% for dose-escalated four-field 3D-CRT 共to total dose of 74 Gy兲. III.B.4. Femoral heads NTCP III.C. Assessment of NTCP values dependence on the relative seriality model parameters The volumetric, radiation dosimetric data, and NTCP of femoral heads for individual treatment techniques discussed Figure 4 shows the effect of varying ␣ / ␤ ratio on rectal NTCP calculated with the relative seriality model. For hy- TABLE V. Average urethral NTCP in various prostate cancer treatment techniques calculated with relative seriality model 共equivalent dose was used in calculation兲. Treatment technique Standard fractionated 3D-CRT 共64 Gy at 2 Gy/fraction兲 Hypofractionated 3D-CRT 共55 Gy at 2.75 Gy/fraction兲 HDR-BT 共Ir-192兲 monotherapy 共4 ⫻ 9.5 Gy兲 LDR-BT 共I-125兲 No. of DVH/patient 7 10 10 36 Medical Physics, Vol. 37, No. 9, September 2010 Average of mean equivalent dose in Gy⫾ S.D 共range兲 Average irradiated volume in cm3 ⫾ S.D 共range兲 Average NTCP in % ⫾ S.D 共range兲 64.2⫾ 0.6 共63.8–65.3兲 59.3⫾ 0.1 共59.2–59.4兲 93.5⫾ 5.7 共83.7–103.4兲 130.4⫾ 5.1 共118.0–139.2兲 5.2⫾ 0.5 共4.6–5.9兲 5.5⫾ 1.1 共4.3–7.5兲 0.8⫾ 0.3 共0.5–1.5兲 0.6⫾ 0.2 共0.2–1.6兲 9.4⫾ 1.1 共8.2–11.2兲 3.6⫾ 0.7 共2.8–5.0兲 11.2⫾ 3.9 共6.5–19.3兲 24.7⫾ 8.0 共12.0–55.1兲 5133 Takam et al.: Normal tissue complications following prostate cancer irradiation 5133 TABLE VI. Average femoral heads NTCP and in various treatment techniques for prostate cancer 共equivalent dose was used in calculation兲. Treatment technique Five-field 3D-CRT 共70 Gy at 2 Gy/fraction兲 No. of DVH/patient Average of mean equivalent dose in Gy⫾ S.D 共range兲 Average irradiated volume in cm3 ⫾ S.D 共range兲 Average NTCP in % ⫾ S.D 共range兲 14 30.2⫾ 7.2 共20.4–44.0兲 204.0⫾ 68.9 共101.5–372.8兲 0.2⫾ 0.4 共0.0–1.3兲 33.5⫾ 7.1 共17.3–39.0兲 39.4⫾ 1.4 共38.4–40.3兲 121.9⫾ 55.7 共38.6–217.2兲 117.7⫾ 7.3 共112.6–122.8兲 0.02⫾ 0.02 共0.0–0.05兲 0.06⫾ 0.04 共0.04–0.09兲 Dose-escalated 3D-CRT A. Total dose of 70 Gy 10 B. Total dose of 74 Gy 2 pofractionated 3D-CRT, variation of ␣ / ␤ ratio from 1 to 10 Gy causes around 5% change in rectal NTCP. However, a smaller change 共ⱕ2%兲 in rectal NTCP was observed either for hypofractionated 3D-CRT and HDR-BT considering ␣ / ␤ ratio for rectum ⱖ5 Gy 共typically assumed for normal tissues兲. If ␣ / ␤ is less than 3 Gy then the NTCP difference between the techniques will only be greater, with EBRT resulting in worse NTCP. In case of varying the value of the s parameter, the rectal NTCP for hypofractionated 3D-CRT appears to have a linear relationship with the s parameter. The rectal NTCP varies from approximately 0.3%–1.6%, i.e., around 1.3% change, for the whole range of the s parameter values from 0 to 1 共Fig. 5兲. The relationship between the s parameter and the rectal NTCP appears to be exponential for HDR-BT. However, small changes only in rectal NTCP 共⬍1.2%兲 were observed with increasing of the s parameter value from 0.1 to 1.0. This full extent of the s parameter values is unrealistic as rectum is considered a serial organ 共s values closer to 1兲 rather than parallel 共s values closer to 0兲. The variations in NTCPs between s values of 0.5 and 1 are less then 0.5% for FIG. 4. A plot shows changes in rectal NTCP 共%兲 in fractionated 3D-CRT 共쎲兲 and HDR-BT monotherapy 共䊐兲 corresponding to variation in the value of rectal ␣ / ␤ ratio. Medical Physics, Vol. 37, No. 9, September 2010 hypofractionated EBRT and less than a percent for HDR-BT, therefore not contributing to the final error bar significantly. Finally, Fig. 6 shows the relationship between value of parameter k and rectal NTCP as predicted by the relative seriality model. Variation of the value of this parameter from 1 to 20 causes considerable change in rectal NTCP for hypofractionated 3D-CRT especially when the value of parameter k is smaller than 10. Contrarily, varying the value of parameter k in the same range has a much smaller effect in rectal NTCP for HDR-BT with approximately 1%–2% change. For values of k less than 10, the difference in NTCPs between HDR-BT and hypofractionated EBRT will only be accentuated/increased. As a result, we believe that the NTCP differences between modalities 共EBRT and BT兲 are valid even within the model uncertainties. IV. DISCUSSION From all rectal differential DVHs evaluated for standard four-field 3D-CRT, it was observed that some DVHs contained a dose peak at the Deq around 30–40 Gy while some of them had a peak at the Deq of 60–65 Gy. For those DVHs FIG. 5. A plot shows changes in rectal NTCP 共%兲 in fractionated 3D-CRT 共쎲兲 and HDR-BT monotherapy 共䊐兲 corresponding to variation in the value of parameter s. 5134 Takam et al.: Normal tissue complications following prostate cancer irradiation FIG. 6. A plot shows changes in rectal NTCP 共%兲 in fractionated 3D-CRT 共쎲兲 and HDR-BT monotherapy 共䊐兲 corresponding to variation in the value of parameter k. which had the peak around intermediate Deq range, the average rectal NTCP was around 1%, while those rectal DVHs which had the peak around the prescribed tumor doses have average rectal NTCPs in a range of 2%–4%. Similarly, most of the bladder DVHs for standard fractionated 3D-CRT had the dose peak around the prescribed tumor doses of 60–65 Gy which resulted in a bladder NTCP of approximately 2%, while those DVHs having a peak around 30–40 Gy resulted in NTCP of less than 2%. In addition, reduction of normal tissue complication risk following external beam radiotherapy can also be achieved by decreasing the normal tissue volume that might be exposed to therapeutic radiation dose, i.e., reducing the treatment margin. With hypofractionated four-field 3D-CRT, dose-volume distributions of the rectum, bladder, and urethra were similar to that of standard fractionated four-field 3D-CRT, but the irradiated volumes were approximately 11% smaller. Additionally, lower equivalent doses 共maximum of 55 Gy兲 were used to irradiate the prostate which, accordingly, resulted in lower dose exposure of the surrounding normal tissues, which ultimately led to lower estimated probability of complications following the treatment. Since the prostate has been observed to have lower ␣ / ␤ ratio than normal tissues, this gives some advantages to hypofractionated EBRT or HDR-BT as treatment of choice for prostate cancer because both techniques have a potential to yield increased tumor control for a given level of late complications or decreased late complications for a given level of tumor control.33 Results from this study partly confirmed this theory as the estimated NTCP for a particular organ from hypofractionated 3D-CRT was lower than that from standard fractionated 3DCRT. However, it should be noted that there are few reports of higher values of ␣ / ␤ ratio for prostate.34,35 Possible reasons for the lower NTCP estimated in this study include lower average irradiated volumes particularly for the bladder and the use of an ␣ / ␤ ratio of 7.5 for bladder and of 5.4 for rectum. Based on the ␣ / ␤ ratio considerations, the linearMedical Physics, Vol. 37, No. 9, September 2010 5134 quadratic model would predict lower 2 Gy equivalent doses for the hypofractionated schedule used in this study. Outcome analysis of latest randomized trials comparing hypofractionated schedules with conventional fractionation for prostate show quite inconclusive results regarding NTCP. While some trials show no difference between the two schedules in regards to NTCP,36,37 others show better NTCP with hypofractionation38 or only a small increase in certain toxicities and not necessarily on genitourinary ones.39,40 Obviously, NTCP results depend on fraction size too, as really large fraction sizes can induce toxicity. However, more studies and longer follow-up are needed, especially for the recent trials, to fully validate the efficacy of hypofractionation both NTCP and TCP wise. HDR-BT, either as monotherapy or as a boost to EBRT, has been reported to cause very low rates of severe late toxicity to surrounding normal tissues.41–43 Mean Deq received by rectum from HDR-BT ranged between 50 and 78 Gy, while the mean Deq for urethra ranged similarly between 50 and 73 Gy. DVHs obtained from prostate treatment plans indicated that only small fractions 共approximately 1.5% of total volume兲 of rectum were exposed to high therapeutic doses during the treatment. Therefore, average rectal NTCP following HDR-BT predicted was much smaller than that following EBRT. This conclusion is in agreement with clinical findings. Data based on a review of clinical results following HDR-BT as a boost to EBRT indicate a small prevalence of severe long term toxicity.7 Furthermore, chronic toxicities after HDR-BT as monotherapy for prostate cancer have been reported to less than LDR-BT after a median follow-up period of 35 months.11 Most complications observed in the HDR monotherapy patients were low grade toxicity and none of the patients experienced grade 4 toxicities. With a median follow-up of 4 yr, the most severe late complication observed in patients treated with HDR-BT was urethral stricture with a 5 yr actuarial risk of 7% and no patient experienced late severe rectal complications.41 The incidence of urological complications observed in the previous report was obvious when it is related to differential DVHs assessment observed in this study where average Deq received by the urethra from the treatment was as high as 120 Gy representing the highest received by all normal tissues. For LDR-BT using I-125 permanent radioactive seeds, radiotherapy parameters such as average BEffD and Deq were similar to HDR-BT although rectal and urethral irradiated volume were slightly smaller. Dose-volume distribution of LDR-BT in the rectum appeared to be more inhomogeneous compared to other techniques and ranged widely from 30 to 130 Gy. Although a wide range of equivalent dose was delivered to rectum, only small fractions 共approximately 4% in total兲 were irradiated to the prescription dose. Hence, a small value of average rectal NTCP ensued. For urethra, during prostate irradiation, a part of the urethra located inside the prostate 共prostatic urethra兲 may receive the same dose which was given to the prostate especially with the EBRT. As a result, higher NTCP values were observed from DVHs assessment for the urethra than other 5135 Takam et al.: Normal tissue complications following prostate cancer irradiation irradiated organs. For brachytherapy, planning was done in such a way that dose to the urethra was minimized. However, some fractions of the urethra were still irradiated with the equivalent doses in a range of 120–140 Gy for LDR-BT and 110–130 Gy for HDR-BT, which were considerably higher than the doses that other organs received. Accordingly, it was indicated by the NTCP model that severe complications of urethra following prostate irradiation are more likely to be observed than that of other surrounding healthy organs. With LDR-BT, approximately 3% of urethral volume was irradiated to equivalent doses in the range of 100–150 Gy, clearly the highest among the doses received by other OARs. The average urethral NTCP of 24.7% predicted is higher than severe complication rates reported clinically. The discrepancy is likely to be attributable to the lack of published urethral specific model parameters. The average urethral NTCP of 24.7% predicted by this model is, however, consistent with reports of low grade 共grade 0–grade 2兲 urinary toxicity 共incontinence兲 after I-125 LDR-BT range widely between 0%–40%.44,45 Dose-escalated four-field 3D-CRT to a total dose of 70 and 74 Gy is currently used at our center for treatment of low and intermediate/high-risk prostate cancer. The planning target volume is reduced after 64 Gy to avoid exposure of surrounding normal tissues to the full prescription dose. Distribution of equivalent doses over the volume of rectum and bladder was therefore similar to that of standard fractionated and hypofractionated 3D-CRT. Although PTV was reduced in order to minimize the healthy tissue damage, some portions of rectum and bladder volume were still exposed to high doses resulting in a higher prediction of rectal and bladder NTCP. Zelefsky et al.5 reported 5 yr actuarial likelihood of development of grade 2 and grade 3 late GI toxicities of 11% and 0.75%, respectively, following the prostate treatment using dose-escalated 3D-CRT up to 81 Gy. In addition, the 5 yr actuarial likelihood of development of grade 2 and grade 3 late GU toxicities was 10% and 3%, respectively. Our differential DVHs assessment showed NTCP ranges of 1.2%– 6.1% and 1.3%–9.1% for the rectum and bladder, respectively, which are consistent with the rates of severe late GI and GU toxicities. Michalski et al.46 recently investigated dose-volume effects in radiation induced rectal injury. They reviewed several published data on rectal injury and estimated parameters for the Lyman–Kutcher–Burman NTCP model. While the s value of the relative seriality model used in this study for estimation of NTCP for rectal complications is slightly lower than the n parameter of the Lyman–Kutcher–Burman model in their work, it yields NTCPs within a similar range for dose-escalated 3D-CRT. Severe complications of femoral heads have been rarely reported. Corresponding differential DVHs from our doseescalated 3D-CRT treatment plans indicated that they would normally receive equivalent doses in a range of 30–40 Gy explaining the lack of reports of severe complications. In addition, the complication rates for femoral heads are lower than those observed compared to other OARs because the Medical Physics, Vol. 37, No. 9, September 2010 5135 DVHs show that only 11%–14% of the femoral head were irradiated to the prescription doses, the remainder receiving lower physical and therefore equivalent doses. While the NTCP increases with the dose 共from 0.02% to 0.06% for 70 and 74 Gy, respectively兲, a larger increase in NTCP has been observed for larger volumes of the femoral heads irradiated to the prescribed dose of 70 Gy 共0.2% for 204 cm3 and 0.02% for 122 cm3兲. Borghede and Hedelin47 reported the estimated femoral heads dose of 49 Gy from 3D-CRT treatment technique 共total dose of 70 Gy with standard fractionation兲 and 64.8 Gy with hypofractionated 共2.4 Gy/fraction兲 for prostate cancer. Out of 184 patients involved in their study, only one patient 共0.5%兲 experienced osteonecrosis of the hip joint 18 months after the treatment and was suspected as a result of three-field treatment technique which increased the dose to femoral heads compared to four-field technique. A range of mean doses similar to ours, received by femur head and neck during prostate treatment, was reported by Gershkevitsh et al.48 For a dose prescribed to target of 64 Gy with different plans, the mean doses to this OAR were in the range of 3–34 Gy, the maximum mean dose falling within the range reported in this study. Bedford et al.49 reported the use of the Lyman model to estimate a complication probability of femoral heads for different radiation treatment plans of conformal radiotherapy for prostate cancer. In his report, the NTCP of femoral heads was generally small 共⬍0.1%兲 except for a few plans with NTCP of up to 5.5%. Luxton et al.50 also reported very small NTCP probability 共up to 0.05%兲 of femoral heads as a result of 3D-CRT for prostate carcinoma. Testing for the sensitivity of NTCP predictions using the relative seriality model, the values of ␣ / ␤ ratio and s and k parameters for the rectum were varied within the total range and changes in estimated rectal NTCP in hypofractionated 3D-CRT and HDR-BT were investigated. In case of ␣ / ␤ ratio for rectum which is typically assumed to be larger than that for the target organ 共prostate兲, increasing from its default value 共5.4 Gy兲 to the maximum value 共10 Gy兲 had little effect on estimated rectal NTCP in both hypofractionated EBRT and HDR-BT. It may be assumed that within the typical range of ␣ / ␤ ratio 共5–10 Gy兲 for rectum, the estimated rectal NTCP is virtually independent to rectal ␣ / ␤ ratio. The magnitude of variation in rectal NTCP in both techniques as a result of changes in the s parameter was not substantial as only around a 1.2% increase in rectal NTCP was observed. Variations of the k parameter within the expected range 共1–20兲 had greater effect on estimated rectal NTCPs in hypofractionated 3D-CRT than HDR-BT, especially for k ⱕ10. The effect of this dependence on rectal NTCP in HDR-BT was far less pronounced and seems to be virtually independent of the value. For values of k less than 10, the difference in NTCPs between HDR-BT and hypofractionated EBRT will only be increased. V. SUMMARY Results form this study are based on theoretical predictions using available radiobiological models and are intended 5136 Takam et al.: Normal tissue complications following prostate cancer irradiation to provide clinicians with additional information to assist in the selection of a radiation treatment technique and plan for radiotherapy of prostate cancer. 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