Radiobiological evaluation of prostate cancer IMRT and conformal-RT plans using different treatment protocols

Physica Medica xxx (2017) xxx–xxx

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Original paper

Radiobiological evaluation of prostate cancer IMRT and conformal-RT plans using different treatment protocols Panayiotis Mavroidis a,b,⇑, Georgios Komisopoulos c, Courtney Buckey d,e, Margarita Mavroeidi a, Gregory P. Swanson d,f, Dimos Baltas g,h, Nikos Papanikolaou d, Sotirios Stathakis d a

Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC, United States Division of Medical Physics, Karolinska Institutet & Stockholm University, Stockholm, Sweden University Hospital of Larissa and General Hospital of Larissa, Greece d Department of Radiation Oncology, University of Texas Health Sciences Center at San Antonio, TX, United States e Department of Radiation Oncology, Mayo Clinic, Scottsdale, AZ, United States f Baylor Scott & White Healthcare Temple Clinic, Temple, TX, United States g Division of Medical Physics, Department of Radiation Oncology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Germany h German Cancer Consortium (DKTK), Partner Site Freiburg, Germany b c

a r t i c l e

i n f o

Article history: Received 5 April 2017 Received in Revised form 7 June 2017 Accepted 4 July 2017 Available online xxxx Keywords: Prostate cancer IMRT CRT Risk for secondary cancer Radiobiological metrics TCP NTCP

a b s t r a c t The purpose of this study is to evaluate the clinical efficacy of both step-and-shoot IMRT and 3DConformal Radiation Therapy modalities (CRT) in treating prostate cancer using radiobiological measures. Another aim was to estimate the risks for developing secondary malignancies in bladder and rectum due to radiotherapy from the corresponding modalities. The treatment plans of ten prostate cancer patients were developed using IMRT and CRT. For the IMRT plans, two beam energies and two treatment protocols were used (the RTOG 0415 and a most restrictive one proposed by Fox Chase Cancer Center (FCCC)). For the evaluation of these plans, the complication-free tumor control probability, the total probability of injury, the total probability of control/benefit, and the biologically effective uniform dose were employed. Furthermore, based on the dosimetric data of IMRT and CRT, the risk for secondary malignancies was calculated for bladder and rectum. The average risk for secondary malignancy was lower for the bladder (0.37%) compared to the rectum (0.81%) based on all the treatment plans of the ten prostate cancer patients. The highest average risk for secondary malignancy for bladder and rectum was for the CRT6X modality (0.46% and 1.12%, respectively) and the lowest was for the IMRT RTOG-18X modality (0.33% and 0.56%, respectively). The
Grade 2 LENT/SOMA response probability was lower for the bladder than for the rectum in all the plans. For the bladder the highest average value was for the IMRT RTOG18X (0.9%) and the lowest was for the CRT-18X modality (0.1%). For the rectum, the highest average value was for the IMRT RTOG-6X (11.9%) and the lowest was for the IMRT FCCC-18X modality (2.2%). By using radiobiological measures it is shown that the IMRT FCCC plans had the lowest risks for normal tissue complications, whereas the IMRT RTOG had the highest. Regarding the risk for secondary malignancies, the CRT plans showed the highest values for both bladder and rectum. Ó 2017 Published by Elsevier Ltd on behalf of Associazione Italiana di Fisica Medica.

1. Introduction The primary goal of cancer radiation therapy is the eradication of the tumor cells, which can be achieved through several plan options such as different dose prescription protocols, beam arrangements, radiation qualities and treatment modalities.

⇑ Corresponding author at: Department of Radiation Oncology, University of North Carolina, 101 Manning Dr., Chapel Hill, NC 27599-7512, United States. E-mail address: [email protected] (P. Mavroidis).

Organs at Risk (OARs) may receive considerably different dose distributions by these treatment modalities [1–3]. Intensity Modulated Radiation Therapy (IMRT) tends to irradiate large volumes of healthy tissues with low doses of radiation, whereas Conformal Radiation Therapy (CRT) tends to irradiate small volume of healthy tissues with moderate to large doses [4]. Additionally, IMRT has demonstrated superior dosimetric results in sparing OARs than CRT [1]. Although the use of IMRT has become very popular in prostate cancer treatment, the dose limits to critical structures have not

http://dx.doi.org/10.1016/j.ejmp.2017.07.003 1120-1797/Ó 2017 Published by Elsevier Ltd on behalf of Associazione Italiana di Fisica Medica.

Please cite this article in press as: Mavroidis P et al. Radiobiological evaluation of prostate cancer IMRT and conformal-RT plans using different treatment protocols. Phys. Med. (2017), http://dx.doi.org/10.1016/j.ejmp.2017.07.003

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P. Mavroidis et al. / Physica Medica xxx (2017) xxx–xxx

been standardized yet. However, recently the QUANTEC guidelines which provide recommendations for these dose limits from systematic review of dose-volume toxicity related to bladder and rectum have helped in covering this gap [4,5]. Several groups and societies, such as the European Organization for Research and Treatment of Cancer (EORTC) and the Radiation Therapy Oncology Group (RTOG), have been investigating prostate cancer IMRT protocols [6–8]. A recent randomized dose escalation trial, which evaluated radiation toxicity found that the risk of rectal bleeding decreased from 46% to 16% if the volume of rectum receiving at least 70 Gy (V70) was less than or equal to 25% [6,7]. The RTOG 9406 3D-CRT study that implemented this dose constraint reported acceptable toxicity [9]. This has become the standard for many studies involving prostate IMRT protocols (e.g. RTOG 0415). On the other hand, there are treatment protocols, proposed by individual institutions, which use more restrictive constraints, which however, have not been compared with those of the RTOG [10–12]. This is the case of Fox Chase Cancer Center (FCCC), which has used stricter dose constraints than RTOG in order to ensure not only low, moderate or severe OAR complications but also reduce the mild quality of life side effects [13]. In current practice, treatment plan evaluation involves many dosimetric metrics, such as the dose-volume histogram (DVH), maximum, minimum and mean doses as well as dose-volume constraints [14]. These metrics try to quantify the quality of a given plan. Recently, in order to make this set of metrics more complete by accounting for the radiobiological characteristics of the tumors and OARs, the complication-free tumor control (P+), the response probabilities of the individual targets and OARs, the generalized equivalent uniform dose (gEUD) and the biologically effective uni have been proposed as alternative tools in the evalform dose (D) uation of treatment plans [14–17]. These additional metrics have been used to evaluate and classify treatment plans by estimating their expected treatment effects [18–20]. This is achieved through the use of dose-response models and clinically derived parameters [21–24]. Lately, the interest in predicting the risk for secondary malignancies from radiotherapy has been increased. This is due to the data that became available regarding the induction of secondary malignancies following therapeutic irradiation delivered many years ago and the increased survival time for many groups of cancer patients [14]. It has been reported that the risks for secondary malignancies associated with these techniques, may not be the same [14,25,26]. In such a case, models that would estimate the those effects should be used to complement the metrics that predict local tumor control and complications in the normal tissues [27–29]. This approach is supported by many studies, which have suggested that there is a competition between induction of carcinogenic mutations and cellular survival [30–32]. Presently, new treatment modalities such as the Volumetric Modulated Arc Therapy (VMAT) are gaining popularity [33]. However, in this study the 3D-CRT and step-and-shoot IMRT modalities are used for two reasons. First, they are still in use and relevant with respect to the induction of secondary malignancies and second the model parameters used in the analysis were derived from clinical trials that mainly used those two modalities. The objective of this study is four fold: (a) to evaluate the effectiveness of the IMRT and CRT radiation modalities in prostate cancer radiotherapy based on standard dosimetric criteria; (b) to compare the examined radiation modalities and protocols based on radiobiological metrics such as tumor control and normal tissue complication probabilities; (c) to estimate the risk for developing secondary malignancies in bladder and rectum; and (d) to investigate the association of the risks for inducing acute normal tissue complications and secondary malignancies.

2. Materials and methods 2.1. Patient selection For this study, ten consecutive patients, who were treated with radiotherapy for prostate cancer, are analyzed. Each patient underwent a CT scan, which was performed with the patient in the treatment position. All the treatment plans were created using the Pinnacle (Philips Medical Systems, Cleveland, OH) treatment planning system (TPS). A single physician contoured the prostate (GTV), seminal vesicles, rectum, bladder, femoral heads, small bowel, and penile bulb. The clinical characteristics of this patients cohort can be seen in a previous dosimetric analysis, which used an alternative ‘average patient’ approach [6]. In that analysis, the DVHs of the ten patients for each organ were grouped together and averaged. So, an average DVH was calculated for each organ producing the ‘average patient’. In our analysis, the individual patient DVHs were used in the calculations and the individual patient results of the dosimetric and radiobiological metrics were averaged instead. 2.2. Prescription and dose constraint protocols Two different treatment protocols were examined in this work. The first protocol uses the RTOG constraints (RTOG 0415) [7]. The second protocol uses stricter constraints, which have been proposed by Fox Chase Cancer Center and will be denoted here as FCCC [13]. The two protocols will be denoted here as RTOG and FCCC, respectively. As described in a previous publication of the group [6], where the treatment planning process is described more analytically, the planning target volume (PTV) was defined as the GTV with 5 mm margins in the anterior, lateral, superior and inferior directions; and a posterior margin of 3 mm. Per the RTOG protocol guideline, the prescription isodose surface should cover
98% of the PTV. Also, the maximum dose to the PTV volume should not exceed the prescription dose by more than 7%. The prescription used for all the plans was 76 Gy to the 95% isodose line of the PTV, in 38 fractions of 2 Gy. IMRT plans were optimized based on their respective criteria for recommended dose constraints to the rectum, bladder, penile bulb and femoral heads. For bladder and rectum, the dose constraint parameters for the two treatment protocols (RTOG and FCCC) are shown in Table 1. For the femoral head, RTOG did not have any dose constraints, whereas FCCC indicated D10% < 50 Gy. For the penile bulb, RTOG indicated mean dose 52.5 Gy, whereas FCCC indicated D10% < 15 Gy. It should be stated that for the FCCC plans, the priority was to satisfy the dose constraints to the bladder and rectum even if this would result in a violation of the guidelines for the PTV coverage. 2.3. Treatment planning and modalities Six plans were generated for each patient. Two CRT plans (using 6 MV and 18 MV photon beams, respectively) were created based on the RTOG treatment protocol and four IMRT plans. The IMRT plans were optimized using two different energies (6 MV and 18 MV) and two different treatment protocols (RTOG and FCCC). Each of the CRT plans utilized the same template of six coplanar beams, with opposed lateral (90° and 270°) and paired oblique (125° with 305° and 65° with 245°) beams. For this study, the step-and-shoot method was utilized to create the IMRT plans. The number of segments per beam was allowed to vary for each patient. This study was designed to compare the impact of different treatment protocols (RTOG and FCCC) on IMRT optimization and

Please cite this article in press as: Mavroidis P et al. Radiobiological evaluation of prostate cancer IMRT and conformal-RT plans using different treatment protocols. Phys. Med. (2017), http://dx.doi.org/10.1016/j.ejmp.2017.07.003

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P. Mavroidis et al. / Physica Medica xxx (2017) xxx–xxx Table 1 The dose constraints of the RTOG 0415 and FCCC treatment protocols for bladder and rectum [6]. Volume

<15% <25% <35% <50%

Rectum

Bladder

RTOG

FCCC

RTOG

FCCC

75 Gy 70 Gy 65 Gy 60 Gy

65 Gy 52 Gy 40 Gy –

80 Gy 75 Gy 70 Gy 40 Gy

– 65 Gy 52 Gy 40 Gy

use the CRT plans as a benchmark in order to interpret the relative differences observed between the two sets of IMRT plans. Due to the limited potential to further optimize the conformity of the CRT plans, we assumed that the dose distributions would not change significantly and the satisfaction of the FCCC constraints would mainly be achieved through a dose de-escalation. So, the RTOG protocol, which is clinically used, was applied to CRT and one set of the IMRT plans for the initial comparison, whereas the IMRT comparison was performed using the different treatment protocols.

number of OARs could be calculated by the following equation [15,16]:

PI ¼ 1 

NY tumors j¼1


 PðDÞ ¼ exp eecðD2Gy =D50 Þðecln ln 2Þ

ð1Þ

where P(D) is the probability of tumor control or normal tissue complication when the tissue is irradiated uniformly with a dose D, D50 is the dose that induces a 50% response and c is the maximum normalized dose-response gradient. The values of the D50 and c parameters are both organ- and clinical endpointdependent, and are normally derived from clinical data (Table 2). These values are in-line with the recommendations from the QUANTEC reviews, with regards to the clinical endpoints used and the dose-response relations for bladder and rectum [4,5]. Since the values of the radiobiological parameters are determined for a certain fractionation scheme, in order to compare the effectiveness of different dose distributions, these dose distributions must be converted to that fractionation scheme. This is done in Eq. (1) by using the D2Gy (in the literature it is also referred as EQD2Gy), which is the 2 Gy equivalent dose and it is calculated by the following equation [14]:

! 1 þ ad=b

ð2Þ

1 þ a2=b

Mj Y

ð1  P j ðDi Þsj Þ

Dv i 1=s j



Þ

ð3Þ

i¼1

where Norgans is the total number of vital OARs, P j ðDi Þ is the response probability of the organ j having the reference volume and been irradiated by a dose Di as given by Eq. (1). Furthermore, Dv i ¼ DV i =V ref is the fractional subvolume of the organ being irradiated compared to the reference volume for which D50 and c have been calculated, Mj is the total number of voxels or subvolumes in organ j and sj is relative seriality parameter characterizing the internal organ structure of organ j. s  1 indicates a serial structure tissue, whereas s  0 indicates a tissue of parallel structure. Tumors are assumed to have a parallel structure since every clonogenic cell within the tumor volume must be destroyed. Consequently, tumor control probability (TCP) and the overall probability of benefit, PB, could be quantified using the Poisson model [14–16]:

PB ¼

The basic dose-response relation used for tumors and normal tissues is described by the Poisson model as follows [14,18–20]:

ð1  ½1 

j¼1

2.4. Radiobiological treatment plan evaluation

D2Gy ¼ D 

NY organs

Mj Y P j ðDi ÞDv i

! ð4Þ

i¼1

where Ntumors is the total number of tumors or targets involved in the clinical case. The effectiveness of the different treatment plans were evaluated by the radiobiological concept of complication-free tumor control probability (P+), which represents the probability of achieving tumor control without causing damage to normal tissues [15]. Therefore, the P+ index can be calculated by the following equation:

Pþ ¼ PB  PB\I  PB  PI

ð5Þ

 concept is also used The biologically effective uniform dose (D) together with other dosimetric quantities to evaluate the radiobio is defined logical effectiveness of the different treatment plans. D as the dose that causes the same tumor control or normal tissue complication probability as the real dose distribution delivered to  can be calculated by the following analytical the patient. D formula:

~  )D  ¼ ec  lnð lnðPðDÞÞÞ Pð~ DÞ  PðDÞ ec  lnðln 2Þ

ð6Þ

where ~ D denotes the 3-dimensional dose distribution. 2.5. Evaluation of secondary malignancies

where 2 Gy represents the reference dose level used for the determination of the dose-response parameters, D is the physical dose, d is the dose per fraction and a/b is the organ-specific dose that accounts for the fractionation characteristics of the tissue and at which the linear and quadratic components of cell killing are equal. For estimating normal tissue complication probability (NTCP) from non-uniform dose distributions, the relative seriality model was used. Subsequently, the overall probability of injury, PI, for a

In the present study, an LQ model proposed by the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) that takes into account the competing factors of induced DNA mutations and cell survival within the irradiated cells is utilized [14,34,35]. This model is comprised of two terms, of which the first is related to the induction of DNA mutation and the second describes the cellular survival. The mathematical for-

Table 2 Summary of the model parameter values for the prostate cancer case. D50 is the dose that is associated with the 50% response rate, c is the maximum normalized value of the dose-response gradient, and s is the relative seriality parameter [22,23]. Organs

D50 (Gy)

c

s

a/b

Clinical endpoint

PTV Bladder Rectum

52.70 69.56 69.75

4.2 1.7 2.3

– 0.35 0.84

3.0 3.0 3.0

Local control
Grade 2 LENT/SOMA
Grade 2 LENT/SOMA

Please cite this article in press as: Mavroidis P et al. Radiobiological evaluation of prostate cancer IMRT and conformal-RT plans using different treatment protocols. Phys. Med. (2017), http://dx.doi.org/10.1016/j.ejmp.2017.07.003

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Table 3 The values of the a1, a2 and a/b cell survival parameters. a1 and a2 are the linear factors of the DNA mutation and cellular survival processes, respectively. It is assumed that for each OAR, a1/b1=a2/b2 [34–36]. Parameters

Bladder

Rectum

a1 (Gy1) a2 (Gy1) a/b (Gy)

0.006 0.25 7.5

0.017 0.25 4.5

mulation of this model for a fractionated treatment plan is the following:

Effect ¼

! " # D2 D2 exp ða2 D þ b2 Þ a1 D þ b1 n n

ð7Þ

where D is the total dose given in n fractions. The first term above is related with the induction of DNA mutation and the second term describes the cellular survival. a1 and a2 are the linear factors of these two processes, whereas b1 and b2 are the corresponding quadratic factors. Cell survival parameters such as the a/b ratios were found in the literature based on analyses of clinical and experimental data for secondary malignancies [34,36]. Table 3 lists the values of the cell parameters for bladder and rectum [36–38].

3.2. Radiobiological comparisons of the various plans and protocols In the diagrams of Fig. 2, the dose-responses of bladder and rectum are presented for a range of uniform doses for the different radiation modalities. Additionally, the average response of each modality is plotted accompanied by error bars indicating the standard deviations of response and dose within the patient group. In Fig. 3, the individual response probabilities of bladder and rectum are shown for each treatment modality together with the response probabilities PI and P+. In Table 5 and Fig. 3, it can be seen that the probability of tumor control is highest in the CRT modality (99.8%) with the minimum variation (±0.1%) among the patients. Similar results are seen for the IMRT RTOG (99.6%, variation ±0.1%). For the IMRT FCCC modality lower response probabilities are observed (93.4–96.4%) with larger variations (4.7–17.7%). In the FCCC protocol, the lower PB values calculated was a result of using a higher priority in satisfying the more restrictive dose volume constraints of the OARs. As it is shown in Tables 4 and 5, for the treatment plans of the CRT modality, the average values over the ten prostate cancer patients for 6 and 18 MV range between 93.6 and 94.3% for the  of 79.3–80.3 Gy. Similarly, for the treatment plans of P+ for a D the IMRT RTOG modality the P+ values range between 87.2% and  of 75.9–76.1 Gy. Finally, for the treatment plans of 88.5% for a D

3. Results

the IMRT FCCC modality the P+ values range between 90.8% and  of 70.4–71.1 Gy. 93.5% for a D

3.1. Dosimetric comparisons of the various plans and protocols

In Fig. 4, the curves of the total control (PB), total normal tissue complication (PI) and complication-free tumor control (P+) probabilities are presented for the ten prostate cancer patients against  which forces the response curves of the PTV of the different D, treatment plans to coincide [14,16].

The dosimetric statistical results for PTV, bladder and rectum for each of the six plans, are shown in Table 4. Fig. 1 shows the average DVHs of PTV, bladder and rectum for each modality. The dose differences between 6 MV and 18 MV photon plans of the same type were small, rarely greater than 1 Gy in each case, as seen in Tables 4 and 5. However, there was a difference in the bladder and rectal doses between the RTOG and the more restrictive FCCC plans. The differences between the RTOG and FCCC plans for the bladder were small, ranging between 0.5 and 1.4 Gy for 6 MV and 0.7– 2.3 Gy for 18 MV. On the other hand, the rectal doses were much lower for the plans using the FCCC criteria and ranged between 16.0 and 23.3 Gy for 6 MV and 17.7–23.5 Gy for 18 MV. In contrast to the excellent results for the critical structure data, the FCCC plans had poorer PTV homogeneity, with an apparent worsening for the plans with higher energies. The effectiveness of the six examined treatment modalities, namely CRT-6X, CRT-18X, RTOG6X, RTOG-18X, FCCC-6X and FCCC-18X, was assessed based on physical and radiobiological measures. In Figs. 1–3, the six radiation modalities are compared in terms of the DVHs and doseresponse curves of the PTV and the OARs (bladder and rectum).

3.3. Risk of secondary malignancies related to the examined treatments plans and protocols Table 6, presents a summary of the results of the risk for secondary malignancies due to the dose distributions to the bladder and rectum by the different treatment modalities. It appears that in all the modality groups (CRT, RTOG, FCCC), the 18 MV plans are associated with lower risks for secondary malignancies than the 6 MV plans. Also, the average risks for secondary malignancies were lower for the bladder (0.33–0.46%) than the rectum (0.56– 1.12%) in all the cases. Regarding the different modality groups, RTOG and FCCC showed very similar results in bladder (0.33– 0.35% vs. 0.35–0.36, respectively), which are lower than those observed for the CRT modality (0.39–0.46%). In rectum, the lower risks for secondary malignancies were observed for the RTOG

Table 4  for The average values and standard deviations of the mean dose, minimum dose for PTV, maximum dose for bladder and rectum and the biologically effective uniform dose (D) the different radiation modalities are shown. The unit of all the quantities is Gy. Modality

PTV Mean dose

CRT vs IMRT based on the RTOG protocol CRT-RTOG-6X 79.4 ± 1.7 CRT-RTOG -18X 81.5 ± 2.3 IMRT-RTOG-6X 76.1 ± 0.7 IMRT-RTOG-18X 76.2 ± 0.7

Bladder Min. dose

 D PTV

Mean dose

67.6 ± 4.8 66.0 ± 4.1 71.6 ± 3.0 72.9 ± 4.0

79.3 ± 1.1 80.3 ± 1.6 75.9 ± 0.9 76.1 ± 1.0 70.4 ± 7.1 71.1 ± 7.7 75.9 ± 0.9 76.1 ± 1.0

RTOG vs FCCC based on the IMRT modality IMRT-FCCC-6X 76.5 ± 0.7 58.4 ± 16.0 IMRT-FCCC-18X 76.5 ± 0.9 56.5 ± 17.5 IMRT-RTOG-6X 76.1 ± 0.7 71.6 ± 3.0 IMRT-RTOG-18X 76.2 ± 0.7 72.9 ± 4.0

Rectum Max. dose

 D Bladder

Mean dose

Max. dose

 D Rectum

12.7 ± 6.5 12.9 ± 6.4 21.7 ± 8.6 22.5 ± 9.0

76.8 ± 5.2 77.0 ± 5.3 76.0 ± 1.5 75.7 ± 1.5

35.7 ± 4.8 35.4 ± 4.7 39.8 ± 4.9 40.3 ± 5.1

21.2 ± 7.2 21.5 ± 6.3 36.2 ± 5.8 36.3 ± 6.2

79.4 ± 5.2 81.7 ± 5.3 77.0 ± 1.5 76.4 ± 1.5

53.8 ± 4.3 53.8 ± 3.2 57.4 ± 3.5 56.9 ± 2.4

21.2 ± 8.7 21.3 ± 8.4 21.7 ± 8.6 22.5 ± 9.0

77.7 ± 1.7 78.0 ± 2.3 76.0 ± 1.5 75.7 ± 1.5

40.0 ± 5.0 40.4 ± 4.9 39.8 ± 4.9 40.3 ± 5.1

23.5 ± 4.4 22.7 ± 4.9 36.2 ± 5.8 36.3 ± 6.2

77.3 ± 1.7 77.4 ± 2.3 77.0 ± 1.5 76.4 ± 1.5

51.3 ± 2.5 51.2 ± 2.3 57.4 ± 3.5 56.9 ± 2.4

Please cite this article in press as: Mavroidis P et al. Radiobiological evaluation of prostate cancer IMRT and conformal-RT plans using different treatment protocols. Phys. Med. (2017), http://dx.doi.org/10.1016/j.ejmp.2017.07.003

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Fig. 2. The dose-response curves of the bladder and rectum for a range of uniform doses and the estimated average responses of the 10 examined patients, are presented. The different points refer to the treatment plans produced by the CRT6X, CRT-18X and RTOG-6X, RTOG-18X, FCCC-6X, FCCC-18X IMRT treatment modalities. The x and y bars of the points indicate the standard deviations regarding the doses to these organs over the 10 patients (x bars) and the estimated response probabilities over the patient cohort (y bars). The middle and lower diagrams refer to the data region indicated in the upper diagram.

Fig. 1. The cumulative DVHs of the PTV, bladder and rectum, averaged over the 10 examined patients, are presented. The different lines refer to the treatment plans produced by the CRT-6X, CRT-18X and RTOG-6X, RTOG-18X, FCCC-6X, FCCC-18X IMRT treatment modalities.

modality (0.56–0.60%) against (0.80–0.82%) for the FCCC and (0.96–1.12%) for the 3D modalities. Fig. 5, presents the risks for secondary malignancies for bladder and rectum for the individual patients and modalities. In the case of bladder, it can be observed that even though the level of the risk between the different modalities change (highest for the CRT plans, similar for the IMRTs), the distribution within each modality remains almost the same. This feature is also seen to some extent in the case of rectum, where the level of risk is higher and the dis-

Table 5 The average values and standard deviations of the response probabilities of the PTV, bladder, rectum, PI and P+ for the different radiation modalities. The unit of response is expressed in%. Modality

CRT-6X CRT-18X RTOG-6X RTOG-18X FCCC-6X FCCC-18X

Average ± Standard deviation PB

PI,Bladder

PI,Rectum

PI

P+

99.8 ± 0.0 99.8 ± 0.1 99.6 ± 0.1 99.6 ± 0.1 96.4 ± 4.7 93.4 ± 17.7

0.1 ± 0.2 0.1 ± 0.1 0.7 ± 0.7 0.9 ± 1.1 0.7 ± 0.8 0.8 ± 0.8

6.1 ± 4.9 5.4 ± 3.6 11.9 ± 8.4 10.4 ± 5.2 2.3 ± 1.6 2.2 ± 1.9

6.3 ± 5.0 5.5 ± 3.7 12.5 ± 8.5 11.1 ± 5.8 3.0 ± 2.1 3.0 ± 2.1

93.6 ± 5.0 94.3 ± 3.7 87.2 ± 8.4 88.5 ± 5.8 93.5 ± 4.8 90.8 ± 17.9

Please cite this article in press as: Mavroidis P et al. Radiobiological evaluation of prostate cancer IMRT and conformal-RT plans using different treatment protocols. Phys. Med. (2017), http://dx.doi.org/10.1016/j.ejmp.2017.07.003

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Fig. 3. The individual response probabilities of the bladder (upper left), rectum (upper right), complication-free tumor control (P+) (lower left) and tumor control (PB) (lower right), are shown for the examined treatment modalities.

tinction between the different modalities more clear (highest risk for the CRT and lowest for the RTOG plans).

4. Discussion The aim of this study was to evaluate the quality of the CRT and IMRT modalities with respect to their treatment effects (as these are expressed through the TCP and NTCP values) but also with respect to the risk of developing secondary malignancies. While it is uncertain whether we are able to establish firm rectum and bladder dose constraints, it is clear that the less volume of normal organs being irradiated, the lower the toxicity [6,39]. As indicated by a previous study of the group [6], while it appears that CRT can limit the dose to the OARs, depending on the constraints used, the improvement in volume sparing is not necessarily any better with the more conformal IMRT technique [40]. Given that IMRT is more costly, labor intensive and time consuming, it then becomes a question as to whether it is a wise use of resources. Our current study shows that using IMRT with more stringent constraints for bladder and rectum (FCCC protocol) produced very similar radiobiological results with the CRT-RTOG plans (similar P+ values). However, it would be more straightforward to perform a direct CRT vs IMRT comparison using for both the FCCC protocol. The CRT plans were able to meet the RTOG 0415 criteria for rectum and bladder for both the 6 and 18 MV photon beam energies (Table 1). Furthermore, the average doses to the PTV were within the specified criteria. Major deviations were also found within some IMRT plans. For patient plans using the FCCC protocol, the rectum received an average of 13 Gy less than the RTOG protocol.

(Fig. 1) For every dose-volume constraint, the achieved dose was markedly less. This is not a trivial issue, as overall dose and hot spots in critical structures could result in increased toxicity [40–42]. From the present analysis (and our previous dosimetric one [6]), it is derived that CRT techniques can meet those criteria indicating that the use of more complex IMRT techniques do not offer any benefit regarding this issue [40]. However, the present analysis also shows that IMRT can indeed further reduce the doses and volumes receiving high doses of radiation (in order to further reduce severe OAR toxicity) at the cost of greater target volume dose inhomogeneity in challenging cases (Fig. 1). Although many of those results were expected, since the tighter dosimetric constraints of the FCCC protocol would lead to lower doses to bladder and rectum and consequently lower NTCP values. However, the magnitude of the reduction in the expected normal tissue complications and the degree to which the satisfaction of the FCCC constraints would affect the expected tumor control had to be investigated. According to the clinical treatment plans and irradiation protocols that were employed in this analysis, it is shown that the CRT and IMRT RTOG plans deliver high mean doses to the PTV. This finding seems to have an impact on the corresponding results of the radiobiological analysis. More specifically, Figs. 2 and 3 shows that regarding tumor control, the CRT and RTOG modalities show the highest probabilities, overall (average PB = 99.8% and 99.6%, respectively). On the other hand, all the modalities spare the bladder very well (average: PI < 1.0%), whereas the FCCC plans spare optimally the rectum (average: PI = 2.3%). From Fig. 2, it is shown that the use of tighter dose constraints did not have a significant impact on bladder because those doses are associated with negligi-

Please cite this article in press as: Mavroidis P et al. Radiobiological evaluation of prostate cancer IMRT and conformal-RT plans using different treatment protocols. Phys. Med. (2017), http://dx.doi.org/10.1016/j.ejmp.2017.07.003

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Fig. 4. The average dose-response curves of the total tumor control (PB), total normal tissue complication (PI) and complication-free tumor control (P+) are presented for the six radiation modalities examined. The different solid and dashed lines refer to the different treatment plans (CRT: solid, RTOG: short dashes, FCCC:  long dashes). The x-axis corresponds to the biologically effective uniform dose (D) and the vertical lines represent the dose prescription of the different treatment plans.

Table 6 The average values and standard deviations of the risks for secondary cancer of bladder and rectum for the different radiation modalities. The unit of risk is expressed in%. Modality

CRT-6X CRT-18X RTOG-6X RTOG-18X FCCC-6X FCCC-18X

Average ± Standard Deviation Bladder

Rectum

0.46 ± 0.08 0.39 ± 0.10 0.35 ± 0.10 0.33 ± 0.11 0.36 ± 0.10 0.35 ± 0.07

1.12 ± 0.21 0.96 ± 0.14 0.60 ± 0.18 0.56 ± 0.22 0.80 ± 0.23 0.82 ± 0.20

ble response probabilities and also the RTOG plans could meet those constraints too. However, the real impact of the tighter constraints is shown in the case of rectum, where considerably lower doses are achieved by the FCCC plans, which are associated with lower measurable response probabilities. In Fig. 3, it can be noted that the patients showing increased responses are the same within each modality group (CRT, RTOG, FCCC) but they are different between different modality groups. This means that the geometrical characteristics of the different patients are processed in different ways by the three modality

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Fig. 5. The individual risks for secondary malignancy for the bladder (upper) and rectum (lower), are shown for the examined treatment modalities.

groups. The radiobiological results shown in Table 5 and Figs. 2 and 3 were produced by calculating the average of the individual response probabilities. In order to smooth out the impact of any outliers we repeated the radiobiological analysis based on the average dose distribution, creating a type of ‘average patient’. So, for every organ, the DVHs of all ten patients were averaged, creating a single average DVH curve. Based on the results of the ‘average patient’ approach (Fig. 4) it is shown that the response curves of FCCC are now very close to those of the CRT modality. Regarding the induction of secondary cancers following radiotherapy, this study is focused in two organs, located at regions close to the tumor. However, there are studies indicating that a considerable proportion of the secondary tumors occur at further regions [43]. Here, the mathematical model used indicates that the risk of cancer induction against dose is almost bell-shaped due to the fact that a considerable inducible repair exists for the radiation effects that lead to DNA mutation [14]. Fig. 6, illustrates how the average risk for secondary malignancies changes based on the dose distributions to the different patients by the different modalities for different levels of prescribed dose (the dose axis shows the average doses that bladder and rectum would receive for different prescribed doses to the PTV). The vertical lines indicate the average doses from all the plans if each technique. It is apparent that in both the bladder and rectum, low uniform doses (2–10 Gy) are associated with the

Please cite this article in press as: Mavroidis P et al. Radiobiological evaluation of prostate cancer IMRT and conformal-RT plans using different treatment protocols. Phys. Med. (2017), http://dx.doi.org/10.1016/j.ejmp.2017.07.003

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Fig. 6. The average distributions of the risk for secondary malignancy in bladder (upper) and rectum (lower) as a function of dose are presented. The different lines refer to the treatment plans produced by the CRT-6X, CRT-18X and RTOG-6X, RTOG18X, FCCC-6X, FCCC-18X IMRT treatment modalities. The vertical lines indicate the mean doses that are delivered to the bladder and rectum by the examined treatment plans. This thick solid line corresponds to uniform irradiation of the organ.

highest risks for secondary malignancies. However, for nonuniform doses having the mean doses in this range the risks are lower depending on the actual distribution of dose. In both cases, the risk for secondary cancer shows a peak at low mean doses, which gradually diminishes at larger doses. It has to be stated that Fig. 6 it shows the values for the risk after renormalizing the plans for different doses while in the clinic, plans made with different dose prescriptions to the PTV could result in different doses to the OARs than a simple renormalized plan will do. Furthermore, the risks shown in the plot have been calculated using the DVHs of bladder and rectum (not the mean dose) and have been averaged among all the patients. This is the correct way to estimate of the risk of secondary malignancies and there are many studies showing that using average doses instead of the heterogeneous dose distribution for calculating the risk is incorrect. In both OARs, the 3D plans deliver lower mean doses, which however are associated with higher risks for secondary malignancies. Regarding bladder, although the expected treatment responses are lowest for the CRT modality the risk for secondary malignancy for this modality is the highest. A similar behavior is observed for the RTOG modality in rectum. Although this modality delivers the highest dose to rectum (Table 4) and is associated with the highest treatment response probability (Table 5) it shows the lowest risk for secondary malignancies (Table 6, Fig. 6). So, it seems

that at the low dose regions the induction of DNA mutations (which may lead to malignant transformations) dominate over cell kill, whereas at the high doses it is the cell-kill processes that dominate. The results presented in this paper agree with those received for another anatomic site [14], which indicate that radiobiological models describing the competition between induction of DNA mutations and cellular survival should be included in the estimation of the risks for secondary cancer taking into account the non-linearity of the biological response to radiation. Based on Fig. 6, for larger doses than those corresponding to the maximum (peak), the dose-risk curve has a negative slope, which means that the risk for secondary malignancies decreases with dose. This finding goes against the so far general belief that higher dose leads to a greater harm to the patient. This seems to hold for the dose-response curves of the radiation effects where an increase in dose is always associated with an increase in response (Fig. 4). These findings suggest that in certain cases, it may be better to select a treatment plan, which delivers a high dose to a small volume of the organ over a plan, which delivers lower dose to a larger organ volume (given that both plans have similar NTCPs) [25,26]. In other words, in certain cases a CRT technique may be preferable against IMRT when secondary risk cancers are taken into consideration. The results of the present study are in contrast to some of the previous works published in the field, which suggest superiority of IMRT to CRT in terms of normal tissue sparing but they are in line with some other studies suggesting that the clinical outcome results indicate equivalency of the two techniques in terms of normal tissue toxicity [44–47]. More specifically, Doleze et al. [45] studied 553 patients with prostate cancer and concluded that dose escalation with IMRT was associated with improved cancer control in intermediate- and high-risk patients in comparison with 3DCRT, without compromising toxicity. Goldin et al. [46], who studied the outcomes of 457 IMRT and 557 CRT patients concluded that post-prostatectomy IMRT and CRT achieved similar morbidity and cancer control outcomes and that the potential clinical benefit of IMRT in this setting is unclear. Zhu et al. [47], who compared 3D-CRT and IMRT with different protocols concluded that they were generally comparable in terms of both the PTV coverage and normal tissue-sparing. It is known that all the existing TCP and NTCP models have been built on some assumptions and they do not account for all the biological mechanisms. This has an impact on the determination of the model parameters of the different tumors and tissues. Additionally, there are uncertainties imposed by inaccuracies in the patient setup and treatment delivery during radiotherapy and the lack of knowledge of the inter-patient radiosensitivity. Consequently, the determined model parameters and the corresponding dose-response curves are characterized by confidence intervals. The results of this study depend on the accuracy of the radiobiological models and the parameters that describe the dose-response relations of the different tumors and normal tissues. However, most of those parameters have been derived from recently published clinical studies, where the confidence intervals have been reduced.

5. Conclusions IMRT plans optimized according to the RTOG 0415 criteria showed similar dosimetric results with the CRT plans, both of which satisfied the constraints imposed for the bladder and rectum. It is suggested that general constraints are not suitable for optimally sparing the rectum using IMRT. However, the additional sparing of the OARs through the use of tighter dose constraints is

Please cite this article in press as: Mavroidis P et al. Radiobiological evaluation of prostate cancer IMRT and conformal-RT plans using different treatment protocols. Phys. Med. (2017), http://dx.doi.org/10.1016/j.ejmp.2017.07.003

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associated in many cases with a higher inhomogeneity in the target volume. The radiobiological analysis showed that the treatment modalities that were more effective regarding the treatment effects (TCP, NTCP, etc) did not show similar results regarding the risk for inducing secondary malignancies. Consequently, the optimization of different treatment modalities and plans, which is currently performed based on their treatment effects, should be complemented by the estimation of the corresponding risks for developing secondary malignancies.

Conflict of interest statement The authors have no conflicts of interest to disclose.

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Please cite this article in press as: Mavroidis P et al. Radiobiological evaluation of prostate cancer IMRT and conformal-RT plans using different treatment protocols. Phys. Med. (2017), http://dx.doi.org/10.1016/j.ejmp.2017.07.003