Year : 2009 | Volume
: 5 | Issue : 2 | Page : 78--84
Normal tissue complication probability: Does simultaneous integrated boost intensity-modulated radiotherapy score over other techniques in treatment of prostate adenocarcinoma
KS Jothy Basu, Amit Bahl, V Subramani, DN Sharma, GK Rath, PK Julka
Department of Radiation Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi - 110 029
Aim: The main objective of this study was to analyze the radiobiological effect of different treatment strategies on high-risk prostate adenocarcinoma. Materials and Methods: Ten cases of high-risk prostate adenocarcinoma were selected for this dosimetric study. Four different treatment strategies used for treating prostate cancer were compared. Conventional four-field box technique covering prostate and nodal volumes followed by three-field conformal boost (3D + 3DCRT), four-field box technique followed by intensity-modulated radiotherapy (IMRT) boost (3D + IMRT), IMRT followed by IMRT boost (IMRT + IMRT), and simultaneous integrated boost IMRT (SIBIMRT) were compared in terms of tumor control probability (TCP) and normal tissue complication probability (NTCP). The dose prescription except for SIBIMRT was 45 Gy in 25 fractions for the prostate and nodal volumes in the initial phase and 27 Gy in 15 fractions for the prostate in the boost phase. For SIBIMRT, equivalent doses were calculated using biologically equivalent dose assuming the α/β ratio of 1.5 Gy with a dose prescription of 60.75 Gy for the gross tumor volume (GTV) and 45 Gy for the clinical target volume in 25 fractions. IMRT plans were made with 15-MV equispaced seven coplanar fields. NTCP was calculated using the Lyman-Kutcher-Burman (LKB) model. Results: An NTCP of 10.7 ± 0.99%, 8.36 ± 0.66%, 6.72 ± 0.85%, and 1.45 ± 0.11% for the bladder and 14.9 ± 0.99%, 14.04 ± 0.66%, 11.38 ± 0.85%, 5.12 ± 0.11% for the rectum was seen with 3D + 3DCRT, 3D + IMRT, IMRT + IMRT, and SIBIMRT respectively. Conclusions: SIBIMRT had the least NTCP over all other strategies with a reduced treatment time (3 weeks less). It should be the technique of choice for dose escalation in prostate carcinoma.
|How to cite this article:|
Jothy Basu K S, Bahl A, Subramani V, Sharma D N, Rath G K, Julka P K. Normal tissue complication probability: Does simultaneous integrated boost intensity-modulated radiotherapy score over other techniques in treatment of prostate adenocarcinoma.J Can Res Ther 2009;5:78-84
|How to cite this URL:|
Jothy Basu K S, Bahl A, Subramani V, Sharma D N, Rath G K, Julka P K. Normal tissue complication probability: Does simultaneous integrated boost intensity-modulated radiotherapy score over other techniques in treatment of prostate adenocarcinoma. J Can Res Ther [serial online] 2009 [cited 2021 Sep 26 ];5:78-84
Available from: https://www.cancerjournal.net/text.asp?2009/5/2/78/52789
Adenocarcinoma of the prostate is a slowly proliferating tumor with limited radio sensitivity, almost close to that of normal tissues. Higher doses of radiation have been associated with a better tumor control.  Four randomized trials have demonstrated improved prostate-specific antigen (PSA) relapse-free survival outcomes in patients treated with escalated radiation doses. ,,, Long-term results of single-institution trials using radiation doses up to 86.4 Gy have shown that higher doses are associated with an improved tumor control and a reduction in the risk of distant metastases. ,, But, the anatomic location of the prostate restricts the dose that can safely be delivered without exceeding the tolerance limits of surrounding critical structures. Conventionally, prostate tumors are treated with a two-phase treatment plan, with initial whole- pelvis treatment followed by a boost. Conventional techniques including three-dimensional conformal radiotherapy (3DCRT) are limited in their ability to deliver high doses to the prostate, due to the normal tissue complications. However, the advent of intensity-modulated radiotherapy (IMRT) has paved the way for dose escalation while keeping the critical structure doses within the tolerance limit. Zelefsky et al. have shown that IMRT significantly reduced the gastrointestinal (GI) and genitourinary (GU) toxicities compared to 3DCRT. Burman et al. have shown that IMRT significantly decreases the rectal morbidity even with high prescription doses. Recently, Mohan et al. and Wu et al. suggested a single-phase approach called as simultaneous integrated boost IMRT (SIBIMRT) for the head and neck cancers, which increases the target dose conformity while simultaneously increasing the critical structure sparing.  SIBIMRT has certain advantages over a two-phase strategy and few of them are listed below:
Single-plan treatment avoids the need for separate boost planning and decreases the time spent by the physician and physicist in planning, evaluation, and verification.It takes advantage of IMRT's ability to conform the prescribed dose to target volumes and superior critical structure sparing.It can deliver different doses to different target volumes in a single plan.The overall treatment time is decreased compared to the two-phase strategy, which may result in a better local control rate.Organs at risk (OAR) receive a lower dose per fraction, rather than a high dose per fraction followed by a low dose per fraction, which decreases the normal tissue complications.Integrated planning finds better mathematical solutions than the two-phase planning, resulting in better dose distributions.
The main objective of this study is to compare different combinations of conventional two-phase treatment plans in prostate adenocarcinoma patients with SIBIMRT in terms of tumor control probability (TCP) for prostate tumors and normal tissue complication probability (NTCP) for the bladder and rectum with equivalent dose prescriptions.
Materials and Methods
Ten cases of high-risk prostate adenocarcinoma treated earlier were selected for this dosimetric study. Four different boost strategies were designed for this study. All the contouring and conventional and inverse planning were made with Eclipse TM TPS (Varian Associates, Palo Alto, CA, USA). The four different boost strategies used in this study were (i) simple four-field box technique covering the prostate and the regional lymph nodes followed by a 3DCRT boost treating the prostate alone (3D + 3DCRT); (ii) four-field box technique followed by an IMRT boost (3D + IMRT); (iii) IMRT designed to treat the contoured target volumes followed by an IMRT boost to the prostate (IMRT + IMRT); and (iv) simultaneous integrated boost IMRT (SIBIMRT). The clinical target volume (CTV) was given a uniform margin of 1 cm except posteriorly, where a margin of 0.5 cm was given to increase the rectal sparing. The volumes included in the respective techniques are given in [Table 1]. CTV1 included the prostate, gross extracapsuar disease, and proximal seminal vesicles. CTV2 included distal seminal vesicles and periprostatic lymph nodes. The prescription doses were 45 Gy in 25 fractions for the initial phase and 27 Gy in 15 fractions for the boost phase for all the strategies except for the SIBIMRT. The equivalent doses for the SIBIMRT were calculated using the classical biologically equivalent dose (BED) equation (1) given below:
where D is the total dose and d is the dose per fraction. The α/β value was assumed as 1.5 Gy, based on the most recent data available for prostate adenocarcinoma (1.5 Gy at 95% CI 0.8-2.2 and 1.49 at 95% CI 1.25-1.76). , These reported values are substantially lower than the traditionally accepted value of 10 Gy for most tumor cells. The reevaluated value of the α/β ratio is now even lower than the best estimate value for normal tissue (α/β = 3 Gy). The low α/β ratio for prostate cancer might be explained by the low cell cycle rate, and high proportion of cells in the G 0 phase of the cell cycle.
Treatment planning was done for the different techniques as follows.
3D + 3DCRT
In this two-phase strategy, the initial phase was planned with the conventional four-field box technique (i.e., anteroposterior (AP), posteroanterior (PA), right lateral, and left lateral) with 15-MV X-rays. A dose of 45 Gy in 25 fractions was prescribed to the 95% isodose surface. This initial phase was followed by a boost dose of 27 Gy in 15 fractions for CTV1 with three 15-MV fields shaped with multi leaf collimator (MLC) (AP, right lateral and left lateral), avoiding the posterior field to decrease the rectal dose. The field portals and target volumes contoured are shown in [Figure 1a],[Figure 1b],[Figure 1c],[Figure 1d].
3D + IMRT
The initial phase was planned similar to the initial phase of the previous strategy. The boost phase was planned to be delivered with IMRT with seven equally spaced 15-MV coplanar fields. The dose--volume constraints used for this plan are given in [Table 2]. The field placement is shown in [Figure 2].
IMRT + IMRT
This involved initial IMRT to CTV1 and CTV2 followed by a IMRT boost to the CTV1. The dose was kept same as in other techniques (45 Gy + 27 Gy). The field placement was same as in other IMRT plans used in this study. The dose-volume constraints used for the initial phase of IMRT are given in [Table 2]. Even though it was possible to use the base dose option available in Eclipse TPS to incorporate the dose delivered in the initial phase of the treatment in the optimization of the boost plan, it was deliberately avoided as it might have produced unacceptable hot and cold spots within the target.
This single-phase strategy was planned to deliver a dose of 60.75 Gy (2.43 Gy/fraction) to CTV1 and 45 Gy (1.8 Gy/fraction) to CTV2 in 25 fractions. Field placements were similar as in other IMRT plans made in this study. The dose-volume constraints used for this planning are given in [Table 2].
Radiobiological models were used to evaluate the results. We used equivalent uniform dose (EUD)-based mathematical models, due to the simplicity, versatility, and also the ability to use the same model for NTCP calculations. The original definition of the EUD was based on the mechanistic formulation using the linear-quadratic (LQ) cell survival model. The concept of the EUD introduced by Niemierko is defined as 'the dose which when distributed uniformly across the target volume causes the survival of the same number of clonogens as the non-uniform dose distribution.' Niemierko extended the concept of the EUD to apply to normal tissues and tumors as well, and it is known as the generalized EUD.  The mathematical expression of the generalized EUD is given in Equation 2:
where V i is a unitless partial volume receiving dose D i in Gy and a is a unitless tumor or normal tissue-specific parameter that describes the dose-volume effect. For a tumor, it indicates the dose, which results in the same cell-kill as the nonuniform dose distribution; for normal tissues, it indicates the dose that results in the same probability of complications. The EUD approaches the maximum dose when a increases to a large positive number and approaches the minimum dose when it decreases to a large negative number; it approaches the mean dose when a equals 1 and approaches the geometric mean when a equals 0.
EUDs were calculated from differential dose volume histograms (DVH) with a = 8.33 for the rectum and a = 2 for the bladder. For SIBIMRT, the concept of voxel equivalent dose was used to calculate the EUD to compare the nonstandard fractionation dose to the standard fractionation dose (2 Gy/fraction) by converting the individual voxel doses to conventional fractionation doses using the BED with an α/β value of 1.5, 6, and 3.9 for the prostate tumor, bladder, and rectum respectively.
The TCP was calculated using the formula given below (equation 3) with D 50 = 46.3 and γ50 = 0.95 as estimated in the work of Okunieff et al ,  where D ijk is the dose received by the ijk th voxel and N is the total number of voxels in the structure of interest. For SIBIMRT, D ijk is the equivalent dose calculated using the BED to account for the nonstandard fractionation:
The NTCP was calculated using the Lyman-Kutcher-Burman (LKB) model as follows (equation 4):
In the above equation (5), D is the EUD delivered to the structure of interest (calculated using Equation 2), D 50 is the dose in Gy required to produce a complication probability of 50% after 5 years, and m is a unitless parameter accounting for the volume effect (determining the steepness of the model curve). The parameters used in the calculation of TCP and NTCP are given in [Table 3].
The results are summarized in [Table 4],[Table 5],[Table 6] for bladder, rectum and prostate respectively. The equivalent dose-volume histograms for four techniques are given in [Figure 1],[Figure 2],[Figure 3] for the bladder, rectum, and prostate respectively. The mean percent difference in the EUD for the bladder is −0.87% ( P -value 0.199), −2.92% ( P = 0.003), −11.58% ( P P = 0.019), −2.91% ( P = 0.003), and −10.75% ( P = 0.002) for 3D + IMRT, IMRT + IMRT, and SIBIMRT, respectively, compared with 3D + 3DCRT. The mean percent difference for PTV1 is −0.87% ( P -value 0.199), −2.92% ( P = 0.003), and −11.58% ( P 5/5 (the probability of 5% complications within 5 years of treatment) parameters used for the conventional treatment of whole bladder and rectum are 65 and 60 Gy, respectively.  The reported rates of cumulative acute Grade ≥ 2 bladder and bowel toxicity seen using conformal radiotherapy of a dose of 64 Gy/32 fractions and 74 Gy/37 fractions are 38% and 30%, and 39% and 33%, respectively. Other studies have reported Grade ≥2 bladder morbidity ranging from 45 to 53% and bowel morbidity ranging from 55 to 56% using standard doses., Late bladder and bowel toxicity of 25 and 21% has been reported after conformal radiotherapy.  IMRT has provided a means for escalating doses up to 86 Gy in treatment of prostate adenocarcinoma.  However, the evaluation of normal tissue toxicity both acute and late is important at such high doses. IMRT has shown to produce the most conformal doses when delivered as SIB.  The TCP and NTCP are useful and essential parameters when planning to deliver very high doses as they provide the risk associated with the treatment. Sometimes such parameters may guide us how much dose we can deliver safely to the tumor. Our results in this study show that SIBIMRT can produce a better dose distribution and the least NTCP when compared with 3D conformal radiotherapy plans and conventional IMRT plans. The slight increase in the TCP values of IMRT plans compared to 3DCRT may be attributed to the increased uniformity and coverage achieved with IMRT plans. Even though SIBIMRT did not increase the TCP much, it has shown a considerable drop in the NTCP of both bladder and rectum. A better sparing of normal tissues has also been reported when using this technique in gynecological malignancies.  Grade 2 GU toxicity of 41% and GI toxicity of 11% have been reported in dose escalation studies in prostate cancer using SIBIMRT.  This compares favorably with results reported at lower doses using more conventional treatments. However, Stavrev et al. have reported a reduction of 5-7% in the TCP when comparing SIBIMRT delivered in the same number of fractionations as the two-phase technique in prostate treatments and suggested that SIB may not be the best treatment strategy unless fractionation schedules are carefully designed. SIBIMRT appears to be a promising technique in prostatic adenocarcinoma. Apart from the enhanced radiobiological effectiveness, SIBIMRT offers an increased machine throughput as the entire treatment is completed in a much shorter time (3 weeks less for prostate cases in our study) and lesser planning and verification time. However, further evaluation using parameters like TCP and NTCP is warranted in bigger trials.
Our study showed that SIBIMRT would produce the least normal tissue complications with almost the same amount of tumor control compared to conventional two-phase treatments. Moreover, SIBIMRT can produce a better physical dose distribution by finding better mathematical solutions by inverse planning techniques. The TCP and NTCP can play a vital role in planning and evaluation when delivering very high doses in individual patients. SIBIMRT can also increase the machine throughput as the treatments are delivered in a shorter period compared to a two-phase treatment.
|1||Hanks GE, Hanlon AL, Pinover WH, Horwitz EM, Price RA, Schultheiss T. Dose selection for prostate cancer patients based on dose comparison and dose response studies. Int J Radiat Oncol Biol Phys 2000;46:823-32.|
|2||Pollack A, Zagars GK, Smith LG, Lee JJ, von Eschenbach AC, Antolak JA, et al . Preliminary results of a randomized radiotherapy dose-escalation study comparing 70 Gy with 78 Gy for prostate cancer. J Clin Oncol 2000;18:3904-11.|
|3||Zietman AL, DeSilvio ML, Slater JD, Rossi CJ Jr, Miller DW, Adams 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.|
|4||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.|
|5||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.|
|6||Zelefsky MJ, Leibel SA, Gaudin PB, Kutcher GJ, Fleshner NE, Venkatramen ES, et al . Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 1998;41:491-500.|
|7||Zelefsky MJ, Hunt MA, Fuks Z. Long-term distant metastases-free survival and cause-specific survival outcomes after high dose conformal radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2006;66:S9.|
|8||Jacob R, Hanlon AL, Horwitz EM, Movsas B, Uzzo RG Pollack. The relationship of increasing radiotherapy dose to reduced distant metastases and mortality in men with prostate cancer. Cancer 2004;100:538-43.|
|9||Burman C, Chui CS, Kutcher G, Leibel S, Zelfesky M, LoSasso T, et al . Planning, delivery, and quality assurance of intensity-modulated radiotherapy using dynamic multileaf collimator: A strategy for large-scale implementation for the treatment of carcinoma of the prostate. Int J Radiat Oncol Biol Phys 1997;39:863-73.|
|10||Mohan R, Wu Q, Manning M, Schmidt-Ullrich R. Radiobiological considerations in the design of fractionation strategies for intensity-modulated radiation therapy of head and neck cancers. Int J Radiat Oncol Biol Phys 2000;46:619-30.|
|11||Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 1999; 43(5):1095-1101.|
|12||Fowler J, Chappell R, Ritter M. Is alpha/beta for prostate tumors really low? Int J Radiat Oncol Biol Phys 2001; 50(4): 1021-1031.|
|13||Niemierko A. Reporting and analyzing dose distributions: A concept of equivalent uniform dose. Med Phys 1997;24:103-10.|
|14||Okunieff P, Morgan D, Niemierko A, Suit HD. Radiation dose-response of human tumors. Int J Radiat Oncol Biol Phys 1995;32:1227-37.|
|15||Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, et al . Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1991;21:109-22.|
|16||Beckdorf V, Guerif S, Leprise E, Cosset JM, Lefloch O, Chauvet B, et al . The GETUG 70 Gy vs 80 Gy randomized trial for localized prostate cancer: Feasibility and acute toxixity. Int J Radiat Oncol Biol Phys 2004;60:1056-65.|
|17||Peeters ST, Heemsbergen WD, van Putten WL, Slot A, Tabak H, Mens JW, et al . Acute and late complications after radiotherapy for prostate cancer: Results of a multicenter randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Oncol Biol Phys 2005;61:1019-34.|
|18||Karlsdottir A, Muren LP, Larsen TW, Dahl O. Late gastrointestinal morbidity after three dimensional conformal radiation therapy for prostate cancer fades with time in contrast to genitourinary morbidity. Int J Radiat Oncol Biol Phys 2008;70:1478-86.|
|19||Cahlon O, Zelefsky MJ, Shippy A, Chan H, Fuks Z, Yamada Y, et al . Ultra - high dose (86.4Gy) IMRT for localized prostate cancer: Toxicity and biochemical outcomes. Int J Radiat Oncol Biol Phys 2008;71:330-7.|
|20||Guerrero M, Li XA, Ma L, Linder J, Deyoung C, Erickson B. Simultaneous integrated intensity modulated radiotherapy boost for locally advanced gynecological cancers: Radiobiological and dosimertic considerations. Int J Radiat Oncol Biol Phys 2005;62:933-9.|
|21||Fonteyene V, Villeirs G, Speelers B, Neve WD, Wagter CD, Lumen N, et al . Intensity modulated radiotherapy as primary therapy for prostate cancer: Report on acute toxicity after dose escalation with simultaneous integrated boost to intraprostatic lesion. Int J Radiat Oncol Biol Phys 2008;1-9 (In press).|