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doi:10.1016/S0360-3016(03)00086-5 3D-CRT PREDICTION OF THE BENEFITS FROM DOSE-ESCALATED HYPOFRACTIONATED INTENSITY-MODULATED RADIOTHERAPY FOR PROSTATE CANCER ALI M. AMER, M.SC.,* JUDITH MOTT, M.SC.,* RANALD I. MACKAY,PH.D.,* PETER C. WILLIAMS,PH.D.,* JACQUELINE LIVSEY, B.M., B.CH., F.R.C.R., JOHN P. LOGUE, M.B., CH.B., F.R.C.R., AND JOLYON H. HENDRY,PH.D., D.SC. *North Western Medical Physics, Clinical Oncology, and Experimental Radiation Oncology, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, England. Purpose: To estimate the benefits of dose escalation in hypofractionated intensity-modulated radiotherapy (IMRT) for prostate cancer, using radiobiologic modeling and incorporating positional uncertainties of organs. Methods and Materials: Biologically based mathematical models for describing the relationships between tumor control probability (TCP) and normal-tissue complication probability (NTCP) vs. dose were used to describe some of the results available in the literature. The values of the model parameters were then used together with the value of 1.5 Gy for the prostate cancer / ratio to predict the responses in a hypofractionated 3 Gy/fraction IMRT trial at the Christie Hospital, taking into account patient movement characteristics between dose fractions. Results: Compared with the current three-dimensional conformal radiotherapy technique (total dose of 50 Gy to the planning target volume in 16 fractions), the use of IMRT to escalate the dose to the prostate was predicted to increase the TCP by 5%, 16%, and 22% for the three dose levels, respectively, of 54, 57, and 60 Gy delivered using 3 Gy per fraction while keeping the late rectal complications (>Grade 2 RTOG scale) at about the same level of 5%. Further increases in TCP could be achieved by reducing the uncertainty in daily target position, especially for the last stage of the trial, where up to 6% further increase in TCP should be gained. Conclusion: Dose escalation to the prostate using IMRT to deliver daily doses of 3 Gy was predicted to significantly increase tumor control without increasing late rectal complications, and currently this prediction is being tested in a clinical trial. © 2003 Elsevier Inc. Radiobiologic modeling, Dose escalation, Prostate cancer, Patient movement. INTRODUCTION The main benefits of three-dimensional conformal radio- therapy (3D-CRT)/intensity modulated radiotherapy (IMRT) techniques are considered to be the avoidance of organs at risk (OARs), for example the spinal cord, rectum, and parotid, as well as the improved conformation, enabling dose “sculpting” around tumors to reduce the irradiated volume. The latter is expected to lead to improved quality of treatment outcome; it also indicates the possibility of dose escalation and improved tumor control probability (TCP) without increasing morbidity. In addition, in the case of prostate tumors, there is evidence that their fractionation sensitivity is high (/ ratio around 1.5 Gy) (1–3) compared to many other tumor types, for which values 4 –16 Gy or more are found (4). Also, the fractionation sensitivity is higher than for most late-reacting normal tissues, so that an increase in dose per fraction should be beneficial in increas- ing dose effectiveness on tumor vs. late morbidity (2). The reasons for this high fractionation sensitivity are associated with the very slow proliferation characteristics of this tumor type. These tumors have a very low labeling index of around 1%, in contrast to most other tumor types, where the values are around 4% or higher (5). Liposarcomas are another example where the fractionation sensitivity is high and the labeling index is also very low (4, 5). In the specific case of prostate cancer, it should be pos- sible to use hypofractionated and accelerated fractionation schedules. This is not only for ease and convenience to patients, but it should also be without detriment to either tumor control or late morbidity, provided that (in the case of the same irradiated volume) total dosage is suitably reduced. Reprint requests to: A. M. Amer, North Western Medical Phys- ics, Christie Hospital NHS Trust, Manchester M20 4BX, UK. Tel: 0044 161 446 3463; Fax: 0044 161 446 3543; E-mail: ali.amer@ physics.cr.man.ac.uk Presented at the 3rd S. Takahashi Memorial International Work- shop on 3-Dimensional Conformal Radiotherapy, December 8 –10, 2001, Nagoya, Japan. A.M.A. was supported by the Libyan government, and J.H.H. was supported by Cancer Research UK. Received Feb 21, 2002, and in revised form Jun 27, 2002. Accepted for publication Jul 31, 2002. Int. J. Radiation Oncology Biol. Phys., Vol. 56, No. 1, pp. 199 –207, 2003 Copyright © 2003 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/03/$–see front matter 199

Prediction of the benefits from dose-escalated hypofractionated intensity-modulated radiotherapy for prostate cancer

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doi:10.1016/S0360-3016(03)00086-5

3D-CRT

PREDICTION OF THE BENEFITS FROM DOSE-ESCALATEDHYPOFRACTIONATED INTENSITY-MODULATED RADIOTHERAPY FOR

PROSTATE CANCER

ALI M. AMER, M.SC.,* JUDITH MOTT, M.SC.,* RANALD I. MACKAY , PH.D.,*PETER C. WILLIAMS , PH.D.,* JACQUELINE LIVSEY, B.M., B.CH., F.R.C.R.,†

JOHN P. LOGUE, M.B., CH.B., F.R.C.R.,† AND JOLYON H. HENDRY, PH.D., D.SC.‡

*North Western Medical Physics,†Clinical Oncology, and‡Experimental Radiation Oncology, Paterson Institute for CancerResearch, Christie Hospital NHS Trust, Manchester, England.

Purpose: To estimate the benefits of dose escalation in hypofractionated intensity-modulated radiotherapy(IMRT) for prostate cancer, using radiobiologic modeling and incorporating positional uncertainties of organs.Methods and Materials: Biologically based mathematical models for describing the relationships between tumorcontrol probability (TCP) and normal-tissue complication probability (NTCP) vs. dose were used to describesome of the results available in the literature. The values of the model parameters were then used together withthe value of 1.5 Gy for the prostate cancer �/� ratio to predict the responses in a hypofractionated 3 Gy/fractionIMRT trial at the Christie Hospital, taking into account patient movement characteristics between dose fractions.Results: Compared with the current three-dimensional conformal radiotherapy technique (total dose of 50 Gy tothe planning target volume in 16 fractions), the use of IMRT to escalate the dose to the prostate was predictedto increase the TCP by 5%, 16%, and 22% for the three dose levels, respectively, of 54, 57, and 60 Gy deliveredusing 3 Gy per fraction while keeping the late rectal complications (>Grade 2 RTOG scale) at about the samelevel of 5%. Further increases in TCP could be achieved by reducing the uncertainty in daily target position,especially for the last stage of the trial, where up to 6% further increase in TCP should be gained.Conclusion: Dose escalation to the prostate using IMRT to deliver daily doses of 3 Gy was predicted tosignificantly increase tumor control without increasing late rectal complications, and currently this prediction isbeing tested in a clinical trial. © 2003 Elsevier Inc.

Radiobiologic modeling, Dose escalation, Prostate cancer, Patient movement.

INTRODUCTION

The main benefits of three-dimensional conformal radio-therapy (3D-CRT)/intensity modulated radiotherapy(IMRT) techniques are considered to be the avoidance oforgans at risk (OARs), for example the spinal cord, rectum,and parotid, as well as the improved conformation, enablingdose “sculpting” around tumors to reduce the irradiatedvolume. The latter is expected to lead to improved quality oftreatment outcome; it also indicates the possibility of doseescalation and improved tumor control probability (TCP)without increasing morbidity. In addition, in the case ofprostate tumors, there is evidence that their fractionationsensitivity is high (�/� ratio around 1.5 Gy) (1–3) comparedto many other tumor types, for which values 4–16 Gy ormore are found (4). Also, the fractionation sensitivity is

higher than for most late-reacting normal tissues, so that anincrease in dose per fraction should be beneficial in increas-ing dose effectiveness on tumor vs. late morbidity (2). Thereasons for this high fractionation sensitivity are associatedwith the very slow proliferation characteristics of this tumortype. These tumors have a very low labeling index of around1%, in contrast to most other tumor types, where the valuesare around 4% or higher (5). Liposarcomas are anotherexample where the fractionation sensitivity is high and thelabeling index is also very low (4, 5).

In the specific case of prostate cancer, it should be pos-sible to use hypofractionated and accelerated fractionationschedules. This is not only for ease and convenience topatients, but it should also be without detriment to eithertumor control or late morbidity, provided that (in the case ofthe same irradiated volume) total dosage is suitably reduced.

Reprint requests to: A. M. Amer, North Western Medical Phys-ics, Christie Hospital NHS Trust, Manchester M20 4BX, UK. Tel:0044 161 446 3463; Fax: 0044 161 446 3543; E-mail: [email protected]

Presented at the 3rd S. Takahashi Memorial International Work-shop on 3-Dimensional Conformal Radiotherapy, December 8–10,

2001, Nagoya, Japan.A.M.A. was supported by the Libyan government, and J.H.H.

was supported by Cancer Research UK.Received Feb 21, 2002, and in revised form Jun 27, 2002.

Accepted for publication Jul 31, 2002.

Int. J. Radiation Oncology Biol. Phys., Vol. 56, No. 1, pp. 199–207, 2003Copyright © 2003 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/03/$–see front matter

199

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Indeed, there is evidence that short hypofractionated treat-ments for prostate cancer can be very effective (6, 7).Successful treatments can be delivered using 50 Gy/16fractions over 21–22 days, i.e., 3.13 Gy/fraction (7, 8). Also,biologically effective dose to tumor might be adjusted up-ward by using 3D-CRT/IMRT techniques to reduce irradi-ated volumes, and hence to keep the effective dose tocritical structures at tolerable levels. Already, dose escala-tion trials (9–14) are providing estimates of the steepness ofthe dose–response curves for TCP and normal-tissue com-plication probability (NTCP) using particular fractionationschedules. A trial is in progress at the Christie Hospital inManchester (UK) to test the hypothesis of the benefits ofdose escalation using accelerated hypofractionated IMRT(7). The evidence in the literature with regard to the factorsfractionation sensitivity, volume effect, and dose–responseslopes for prostate cancer has been used to model theexpected benefits of these conformal, high-biologic-dose,hypofractionated treatments, and these predicted benefitsare described here.

METHODS AND MATERIALS

Treatment outcome predictionThe approach taken was to use biologically based math-

ematical models for describing the relationships betweenTCP and NTCP vs. dose. Then, reasonable values of themodel parameters were chosen, so as to describe some ofthe data sets available in the literature regarding dose esca-lation studies in prostate cancer radiotherapy. This descrip-tion of existing data was then used to predict the responseswhen the parameter values were changed according to thehypofractionated IMRT trial under discussion here. Ac-count was taken also of patient movement between frac-tions.

At each fraction, deviations in the location of the prostateand rectum as a result of setup error and organ motion weresimulated. These deviations were used to determine the newcoordinates of randomly sampled points for the modeledstructure. More than 2000 random points were sampled,resulting in an absolute accuracy in the estimates of TCPand NTCP of better than 0.5. The physical dose to eachpoint was interpolated from the three-dimensional dosematrix for a particular plan, and the biologically effectivedose (BED) was then calculated. After the completion of alltreatment fractions, the BED values were summed for eachpoint and used to calculate the patient TCP and NTCP.

The Webb and Nahum model (15) was used to estimateTCP. This model uses Poisson statistics to calculate theprobability of eradicating all clonogenic cells. The formulaused was the following:

TCP �1

KJ�k�

j�

iexp����exp���jBEDi,k)]

where � is the density of clonogenic cells, presumably

constant (109 cells/cm3) throughout the tumor and for allpatients; � is the volume of element i with uniform dose(CTV [clinical target volume]/number of random points); �j

is the intrinsic radiosensitivity parameter for patient j, sam-pled from a normal distribution with a mean of �0 and astandard deviation of �� (varies with different �/� assumed;see “Results” ); and BEDi,k is the total biologic effectivedose for element i and treatment scenario k. The TCP wasthe average of 1,000 simulated treatment scenarios (K) and10,000 patients (J) having a heterogeneous radiosensitivity.

The NTCP for the rectum was calculated using the rela-tive seriality model (16). This model predicts the probabilityof organ complications, taking into account serial, parallel,or serial/parallel architecture of the functional subunits. Theexpression used was as follows:

NTCP � � 1 � �i

�1 � P�BEDi�s�v� 1/s

where P(BEDi) is the response of the whole organ to theuniform dose distribution BEDi of element i, calculatedusing a logistic model; s is the relative seriality parameter (1for totally serial structures and 0 for totally parallel struc-tures); a value of s � 0.75 was assumed for the rectum (17);and � is the fractional surface area (area of rectal outersurface/number of sample points).

Treatment planningThree different treatment techniques were simulated: (1)

3D-CRT, delivery of the fractional dose to the whole plan-ning target volume (PTV) during the entire treatment; (2)3D-CRT-B, delivery of the fractional dose to the wholePTV for the initial 16 fractions and to the prostate alone forthe remaining fractions or “sequential boost” ; (3) IMRT-B,delivery of the boosted dose to the prostate alone, whereasthe remaining PTV is prescribed the original 50 Gy dose or“simultaneous boost.” The treatment plans were designedbased on the anatomic information of one representativepatient who had undergone conformal radiotherapy treat-ment at this institution.

IMRT-B plans were produced using the inverse-planningmodule, Plato-ITP, of the Plato treatment planning system(Nucletron B.V., The Netherlands) with a 5-field beamarrangement of gantry angles: 180°, 255°, 325°, 35°, and105°. Because only the prostate will receive the boost dose,2 CTVs must be defined: CTV1, which includes the prostateand the seminal vesicles, and CTV2, which consists of theprostate alone. The PTV was grown from CTV1 with mar-gins of 7 mm posteriorly and 10 mm in all other directions.All OARs considered during the optimization process werealso outlined, including the rectum, bladder, and femoralheads. That part of the rectum lying inside the PTV wasoutlined as a separate organ to allow more control over thedose distributions produced during the optimization pro-cess. The optimization algorithm in Plato-ITP was based oniteratively minimizing a least-squares cost function. The

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dose limits and penalty (or importance) weightings appliedto each organ were found in a previous study and have beenshown to produce acceptable plans in patients who would beeligible for this trial.

For each stage of the dose escalation (See trial detailsbelow), the aim of the IMRT plans was to treat the entirePTV to a minimum of 47.5 Gy (95% of the prescribeddose, 50 Gy) and the prostate to �5% of the boost dose,while sparing the OARs as much as possible. Doses to theOARs could be minimized using a combination of max-imum dose limits and dose–volume constraints. How-

ever, because the part of the rectum lying inside the PTVactually abuts the prostate, the maximum dose in thisOAR would necessarily be the minimum dose acceptablein the boost volume. Likewise, the PTV would receiveaverage doses of greater than the prescribed 50 Gy,because doses would increase toward the boost volume.These effects are illustrated in Fig. 1, which shows dosedistributions for a typical patient. Figure 2a shows dose–volume histograms for the prostate and the rectum for theIMRT-B plans alongside the 3D-CRT plan for the stan-dard dose. Doses for the IMRT plans were prescribed to

Fig. 1. (a) Standard 3D-CRT dose distribution (50 Gy in 16 fractions) for a central slice of a typical patient. (b–d) IMRTdose distributions for the various levels of dose escalation. In all cases, the contours outlined are the CTV (at this level,the prostate alone), PTV, bladder (bl), and rectum (rec). The isodoses shown represent 95% of the target PTV dose (50Gy) and 95% of the prostate boost dose. The prescribed boost doses are (b) 54 Gy, (c) 57 Gy, and (d) 60 Gy, deliveredin 18, 19, and 20 fractions, respectively.

201Prostate hypofractionated dose escalation ● A. M. AMER et al.

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the average PTV dose for the 50 Gy plan or to the averageCTV2 (prostate) dose for the dose-escalated plans. Afteroptimization, the theoretical fluence maps for each beamwent through a sequencer to obtain a quantized fluencemap that would be delivered using a step-and-shoot tech-nique.

For comparison purposes, standard conformal 3D-CRTtreatments were also produced on Plato using the same PTVas for the IMRT-B plans. A 4-field beam arrangement withanterior-posterior (AP) and lateral parallel pairs was em-ployed with doses prescribed to the isocenter. At eachgantry angle, the field was shaped to the PTV, with a

physics margin of 6 mm added to ensure that the PTV wascovered by the 95% isodose. This margin was increased to10 mm superiorly and inferiorly to account for the addi-tional falloff in dose in these directions.

Finally, 3D-CRT-B plans were produced using the stan-dard 4-field plan to deliver 48 Gy to the entire PTV in theinitial 16 fractions, with a sequential boost to the prostatealone of 6, 9, or 12 Gy in 3 Gy fractions. The boost fieldswere planned by fitting the collimator leaves to the prostate,using the same physics margins as above to ensure adequatecoverage. Figure 2b gives the dose–volume histograms forthe 3D-CRT-B plans.

Fig. 2. The dose–volume histograms of the prostate (pr) and rectum (rec) for the (a) 50 Gy 3D conformal “4-field” planand the 54, 57, and 60 Gy IMRT-B simultaneous boost plans and the (b) 50 Gy 3D conformal “4-field” plan and the54, 57, and 60 Gy 3D-CRT-B sequential boost plans.

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Movement simulationProstate movement was assumed to be a combination of

setup errors (displacements of bony anatomy with respect tothe treatment field) and organ motion (displacement androtation of the prostate with respect to bony anatomy). Bothsystematic errors (deviation of the pretreatment positionfrom the average treatment position) and random errors(deviation of the prostate position in a particular dose frac-tion from the average position over all fractions) were takeninto consideration.

Systematic and random setup errors were sampled fromnormal distributions with the following standard deviations:2.6, 2.4, and 2.4 mm and 1.7, 1.8, and 2.0 mm in the AP,superior-inferior (SI), and right-left (RL) directions, respec-tively (18). Translation and rotation of the prostate weresimulated again from normal distributions. Standard devia-tions of 2.7, 1.7, and 0.9 mm were used for translation in theAP, SI, and RL directions and 1.0, 2.0, and 4.0 degrees forrotations about the AP, SI, and RL axes (19). It was as-sumed that prostate rotation is correlated with translationand that the apex is the center of rotation.

For the simulation of rectum movement, the same setuperrors used for the prostate were applied. However, fororgan motion of the rectum, it was assumed that the rectumvolume varies on various fractions by expanding/shrinkingsuperiorly and laterally.

RESULTS

Fits of the TCP model to the clinical data (3) for thevarious assumptions of �/� ratios for the prostate are shown

in Fig. 3. The clinical outcomes for patients with PSA �10ng/ml are 48% and 75% for 70 Gy and 78 Gy, respectively.Characteristics of such patients are closer to the criteria forselection of patients for our trial. For the model to predictthe same clinical outcomes regardless of the �/� ratioassumed, the TCP model parameters � (intrinsic radiosen-sitivity, responsible for the position of the curve) and ��

(variation in the radiosensitivity between patients, respon-sible for the slope of the curve) were adjusted. For each �/�ratio and assuming the same clonogenic cell density � � 109

cells/cm3, there is only one unique set of � and �� that canreproduce the same clinical outcomes. The following sets ofparameters (� and ��) were determined: (0.155 and 0.021),(0.271 and 0.029), and (0.301 and 0.040) for prostate �/�ratios of 1.5, 3.0, and 10.0 Gy, respectively.

Using the fitted parameters with an �/� ratio of 1.5 Gy inthe calculations of TCP for the currently applied 3D-CRTtreatment technique produced a reasonable estimate of 42%.On the contrary, using a value of 10 Gy for �/�, the estimateof the TCP% was only 4%. Comparison of these results withclinical experience supports the use of the former (1.5 Gy)for �/�, which is in line with new evidence of a small �/�value for prostate tumors.

For NTCP, it is difficult to fit model parameters to clinicaldata, because the rectum receives a heterogeneous dosedistribution that depends on the treatment technique andprocedure applied. Nonetheless, the curves produced usingthe following relative seriality model parameters s � 0.75,reference volume � 100 cm3, TD50 � 75 Gy, and TD5 � 55Gy produced reasonable conservative estimates of rectal

Fig. 3. Curves of tumor control probabilities calculated with the Web and Nahum TCP model for several prostate �/�assumptions. Shown also are clinical data (square symbols) and the model estimates of TCP for the current 3D-CRTtreatment technique of 50 Gy in 16 fractions (circle symbols).

203Prostate hypofractionated dose escalation ● A. M. AMER et al.

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complications of Grade 2 (RTOG) or greater (Fig. 4). Be-cause the biological effective doses of TD50 and TD5 wereused in the calculation, it was easier to produce the samecurves for the various assumed �/� values. The two clinicalpoints (squares) of 14% and 21% are 70 Gy and 78 Gydelivered in 2 Gy per fraction using a 4-field box for theinitial 46 Gy, the remaining dose was delivered with asmaller 4-field box in the 70 Gy arm and with 3D-CRT6-field technique in the 78 Gy arm. The model parameterswere selected to predict smaller NTCP values than the

clinical outcome for 70 Gy, because in our simulation, thetotal dose was delivered using 3D-CRT 4-field box. TheNTCP estimate for the currently applied 3D-CRT treatmenttechnique is 6%, assuming an �/� � 3.0 Gy for the rectum.

Table 1 shows the estimated TCPs and NTCPs for thevarious dose levels investigated in the trial using the threetreatment techniques. To take into account the uncertaintyin the sensitivity of the prostate and the rectum to fraction-ation, several �/� ratios were used to calculate TCP andNTCP. Also, uncertainties in the position and/or shape of

Fig. 4. Curves of rectal complication probabilities calculated using the relative seriality model for two assumptions ofrectum �/� values. Shown also are clinical data (square symbols) and the model estimates of NTCP for the current3D-CRT treatment technique of 50 Gy in 16 fractions (circle symbols).

Table 1. TCP and NTCP estimates for the different simulated treatment techniques

Dose/fractionation Technique

TCP% (SD)* NTCP% (SD)

�/� � 1.5 �/� � 3.0 �/� � 10.0 �/� � 1.5 �/� � 3.0 �/� � 4.0

50/16† 3D-CRT 42.1 (1.2) 22.1 (0.9) 4.2 (0.2) 9.2 (1.6) 5.9 (1.0) 4.9 (0.8)IMRT 40.4 (0.7) 20.8 (0.5) 3.8 (0.1) 9.8 (1.7) 6.3 (1.1) 5.2 (0.9)

3D-CRT 55.6 (1.1) 36.3 (1.0) 12.2 (0.5) 12.5 (2.0) 8.5 (1.4) 7.3 (1.2)54/18 3D-CRT-B 53.9 (1.4) 34.7 (1.2) 11.5 (0.5) 9.6 (1.8) 6.6 (1.2) 5.6 (1.0)

IMRT-B 47.4 (2.3) 29.2 (1.7) 9.1 (0.7) 7.3 (1.7) 5.1 (1.2) 4.4 (1.0)

3D-CRT 69.0 (0.9) 51.2 (1.0) 23.0 (0.7) 17.0 (2.6) 11.9 (1.9) 10.3 (1.6)57/19 3D-CRT-B 66.0 (1.3) 49.0 (1.4) 21.5 (0.8) 12.0 (2.2) 8.4 (1.5) 7.2 (1.3)

IMRT-B 57.7 (3.4) 40.1 (2.8) 16.3 (1.3) 6.8 (2.0) 4.9 (1.4) 4.3 (1.2)

3D-CRT 79.3 (0.7) 64.7 (0.9) 36.0 (0.8) 22.3 (3.2) 16.1 (2.4) 14.0 (2.1)60/20 3D-CRT-B 77.1 (1.2) 62.0 (1.4) 33.8 (1.1) 14.7 (2.7) 10.6 (2.0 9.2 (1.7)

IMRT-B 63.8 (5.1) 48.0 (4.4) 23.6 (2.5) 6.5 (2.2) 4.9 (1.6) 4.4 (1.4)

* (SD) is the standard deviation due to movement.† The stated doses are prescribed to the PTV for 3D-CRT technique and to the prostate alone for the 3D-CRT-B and IMRT-B techniques

with the remaining PTV prescribed 48 and 50 Gy.

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the modeled organs, because of setup error and organ mo-tion, were incorporated into the calculations.

For all the three treatment techniques, dose escalationincreased the TCP substantially, regardless of the �/� ratioassumed. For the IMRT-B technique, assuming an �/� of1.5 Gy, gains in TCP% of 5%, 16%, and 22% were pre-dicted for the three stages of the trial compared to theestimated outcome of our current practice at the ChristieHospital of 50 Gy in 16 fractions using 3D-CRT.

The estimated TCP values for the 3D-CRT techniquewere generally larger than the TCP values for the 3D-CRT-B and IMRT-B techniques. The reason is that the dosedelivered to the CTV using 3D-CRT is less heterogeneousthan that using the other two techniques (i.e., target move-ment has a negligible effect on the dose delivered to theCTV, because of the use of an adequate PTV). On the otherhand, for the 3D-CRT-B, parts of the CTV could move outof the boosted field in the last fraction(s), thus causingheterogeneous dose distribution in the CTV. Because thefield is boosted only in the last few fractions, the reductionin TCP is small (2%). In the case of IMRT-B, the dosedistribution is deliberately varied (optimized) to minimizehigh doses to normal tissue, and hence the dose delivered tothe prostate is more heterogeneous. Therefore, the TCP issignificantly smaller than that with the other two techniques.The standard deviations in TCP due to movement for thevarious IMRT-B plans increased according to greater het-erogeneity in dose distribution inside the PTV with higherboosted dose. However, the TCP values for the differenttreatment techniques should not be considered separately,but in conjunction with the predicted NTCP.

The probabilities of late rectal complications (�Grade 2RTOG) are shown on Table 1. If the dose were to beescalated using the 3D-CRT technique, the NTCP was pre-dicted to increase substantially (9%–11%, depending on the�/� assumed). Moderate increases were predicted if 3D-CRT-B was used (4%–6%). On the contrary, the use ofIMRT-B to deliver the same escalated dose, but only to theCTV, would result in about the same or even smaller NTCPlevels (up to 3% reduction in NTCP for �/� � 1.5 Gy forthe rectum). This is because the rectum received smallerBED, because of the decrease in fraction size (50/20 com-pared to 50/16).

The inclusion of movement in the calculation of NTCPresulted in two different trends for the 3D-CRT-B andIMRT-B techniques. The calculated NTCP, allowing formovement, decreased with the 3D-CRT-B plans and in-creased with the IMRT-B plans compared to the NTCPcalculated without allowing for movement. The likely rea-son for this is that for 3D-CRT-B, a large portion of therectum was already in the high-dose region, and movementwould spare it for some of the dose fractions. For IMRT-B,movement would cause parts of the rectum to be in thehigh-dose boosted region for some fractions and henceincrease the total dose and NTCP. This shows the impor-tance of including geometric uncertainties in the calculation

of radiobiological indices, especially for nonuniform dosedistributions.

DISCUSSION

The development of 3D-CRT has enabled more sparingof normal tissue from high doses. In the last decade, severaldose escalation trials have been performed to determine themaximum tolerable doses that could be achieved by thesenew techniques in various tumor sites. The outcomes ofprostate dose escalation trials (9–14, 20, 21) are encourag-ing, indicating that higher doses delivered using conformaltechniques lead to higher rates of tumor control, still withacceptable levels of complications.

Five-year outcomes in a dose escalation study using a4-field “box” conformal technique were reported by Hankset al. (9). A model fitted to the results showed that thebNED (biochemical no evidence of disease) rates increasedby 22% when the dose increased from 70 Gy to 76 Gy(using 2 Gy per fraction) for patients who had PSA �20ng/ml.

Pollack et al. also reported a similar dose effect (10):Five-year bNED rates increased by 27% when the dose wasescalated from 70 Gy to 78 Gy for patients who had PSA�10 ng/ml. Doses of 70 and 78 Gy delivered using 2 Gy perfraction are equivalent to about 54 and 60 Gy deliveredusing 3 Gy per fraction (assuming �/� of 1.5 Gy for theprostate tumor). Our prediction of a 22% increase in TCP byescalating the dose from 50 Gy in 16 fractions to 60 Gy in20 fractions is similar to what has been observed clinicallyin the papers discussed above, bearing in mind that ourescalated dose was prescribed to the prostate alone, not tothe whole PTV.

Several reports have been published of late rectal bleed-ing from dose escalation studies using conformal radiother-apy. Jackson et al. (13) reported rectal bleeding for 261 and315 patients treated with minimum target doses of 70.2 and75.6 Gy, respectively, using 1.8 Gy per fraction. The treat-ments were delivered using a conformal 6-field techniqueand 10-mm margins to define the PTV in all directions,except in the posterior direction, where a 6-mm margin wasapplied. Rates of late rectal bleeding (�Grade 2 RTOGscale) at 30 months were 5% and 12%, respectively, for thestated doses.

For a variety of treatment techniques (4 and 6 fields) usedto deliver 1.8 Gy per fraction, Michalski et al. (12) reportedthe rates of rectal bleeding after 68.4 and 73.8 Gy minimumtarget doses. For the group of 135 patients whose CTV inthe first phase of treatment (up to 55.8 Gy) was the prostateand seminal vesicles and in the second phase (remainder ofthe dose) was the prostate alone, the late rectal complica-tions (�Grade 2) were 6% and 7%, respectively. Margins of5 to 10 mm were applied to define the PTV in the twophases.

Most of the previous dose escalation trials used conven-tional daily doses of about 2 Gy per fraction. For total doseshigher than 80 Gy, the treatment times will be prolonged to

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more than 8 weeks. This will add to the inconvenience ofpatients and to the extra costs involved. However, evidenceof a smaller �/� ratio for prostate tumors suggests that itwould be beneficial to hypofractionate the dose to increasethe therapeutic ratio and decrease the overall treatment time(2). The preliminary late toxicity (median follow-up of 18months) of 51 prostate cancer patients who were prescribeda total dose of 70 Gy at 2.5 Gy per fraction and treated usingIMRT showed excellent results with no incidences of rectalbleeding of �Grade 2 and only 4 patients who had minimalrectal bleeding considered to be of Grade 1 (20). Dailytransabdominal ultrasound localization of the prostate wasperformed, which enabled the use of smaller margins. ThePTV margins were 4 mm posteriorly, 8 mm laterally, and 5mm in all other directions. The very low complication ratesobserved, even though for a short follow-up period, couldbe attributed to the use of IMRT and to the small marginsapplied.

To compare the previous three trials to our predictions ofNTCP, the mean doses were assumed to be 3% greater thanthe reported minimum doses, and the �/� ratio for therectum was assumed to be 3 Gy. Therefore, the equivalentdoses if delivered in 3 Gy per fraction (doses rounded to thenearest multiple of 3 Gy) are 57 Gy and 63 Gy for the dosesreported by both Jackson et al. (13) and Michalski et al. (12)and 66 Gy for the dose reported by Kupelian et al. (21). Ourprediction of 16% NTCP for the 60 Gy treatments deliveredby 3D-CRT is higher than the predictions observed clini-cally. This was a result of our conservative choice of modelparameters to be on the safe side. The use of TD50 � 80 Gyand TD5 � 60 Gy described by Emami et al. (22) wouldproduce smaller NTCP values more in agreement with therecently reported outcomes.

The NTCP values predicted for the different stages ofthe trial IMRT-B treatments were small, being around 5%(assuming �/� � 3 Gy for rectum). This is expected,because of the extra sparing of normal tissue and simul-taneous boost that IMRT can provide. A recent study (23)showed that a simultaneously integrated boost using a5-field IMRT technique decreased the rectal NTCP by afactor of 2 compared with a sequential boost used todeliver the last 10 Gy of a 78 Gy total dose to a smallervolume. The possibility of an even higher �/� ratio forthe rectum because of a component of late injury being“consequential” to early reaction, could result in evenlower rates of morbidity.

Systematic errors in the location of the target positioncould have serious effects on the treatment outcome (24)and jeopardize the benefits expected from escalating thedose to a boosted volume. Our simulation showed that up to

6% of further increase in TCP was lost as a result ofmovement. If measures could be taken to track the dailylocation of the target position and correct any displacementfrom its intended position, further increases in TCP wouldbe expected.

This study shows that hypofractionated dose escalationis predicted to substantially improve the tumor controlrate for prostate cancer patients with extensive disease.The use of IMRT can keep the late rectal complication tovery low levels by optimizing the dose inside the treatedvolume. However, patient movement does reduce theoverall benefits, unless movement is explicitly taken intoaccount. The new evidence of a small �/� ratio forprostate cancer and the low rates of morbidity predictedin our simulation with the use of 3 Gy per fraction couldpermit the escalation of the dose even further. This wouldachieve higher tumor control rates that could not beachieved by 2 Gy fractions, because of the constraints ofnormal tissue tolerances. On this basis, a dose escalationtrial has begun, as follows.

The three levels of dose escalation to be addressed are 54Gy/18 fractions, 57 Gy/19, and 60 Gy/20, with 30 patientsin each arm. The escalated doses will be applied to theprostate alone, with the remaining PTV prescribed the stan-dard dose of 50 Gy. The initial cohort of 30 patients will betreated to the first escalated dose with symptom data (bowel,bladder, and potency) assessed using RTOG scales, LENT/SOMA, and the UCLA prostate cancer index, and with PSAlevels assessed at the outset of radiotherapy, then weeklyduring treatment and at 1.5, 3, 6, 9, and 12 months aftertreatment. If, at a minimum follow-up of 9 months, 1 patientor less has Grade 3 bowel or bladder toxicity, the nextcohort of patients will be treated at the next higher doselevel.

Patients with histologically confirmed prostate cancer areeligible for the trial if either Stage T3, N0, M0 or Stage T2,N0, M0 with at least one of Gleason score �7 or 20 PSA 50 ng/ml. Patients should be WHO performance status 0or 1 and not have had previous pelvic radiotherapy or aradical prostatectomy. All patients will receive neoadjuvanthormonal therapy using an LHRH agonist (goserelin acetate3.6 mg s.c. every 28 days) together with initial cypropteroneacetate (100 mg t.d.s. for 2 weeks commencing 1 weekbefore the first LHRH injection) to prevent flare. The dura-tion of hormone treatment will be for at least 3 monthsbefore radiotherapy and will continue to the end of radio-therapy. The maximum allowed duration is 6 months.

The results of this trial will show whether the currentexpectations of its benefits are realized.

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