International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation
Dosimetrically Triggered Adaptive Intensity Modulated Radiation Therapy for Cervical Cancer Karen Lim, MBBS,* James Stewart, MASc,y,z Valerie Kelly, MSc,y,x Jason Xie, MSc,y Kristy K. Brock, PhD,jj Joanne Moseley, BMath,y Young-Bin Cho, PhD,y,x Anthony Fyles, MD,y,x Anna Lundin, MSc,{ Henrik Rehbinder, PhD,{ Johan Lo¨f, PhD,{ David A. Jaffray, PhD,y,z,x,#,** and Michael Milosevic, MDy,x *Department of Radiation Oncology, Liverpool Hospital, Sydney, Australia; yRadiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; z Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada; xDepartment of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; jj Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan; {RaySearch Laboratories AB, Stockholm, Sweden; #Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; and **Techna Institute for the Advancement of Technology for Health, Toronto, Ontario, Canada Received Mar 18, 2014, and in revised form May 16, 2014. Accepted for publication May 20, 2014.
Summary High-precision image guided radiation therapy has the potential to reduce treatment side effects in cervical cancer. However, uptake of intensity modulated radiation therapy has been limited because of target underdosing concerns in the setting of very narrow
Purpose: The widespread use of intensity modulated radiation therapy (IMRT) for cervical cancer has been limited by internal target and normal tissue motion. Such motion increases the risk of underdosing the target, especially as planning margins are reduced in an effort to reduce toxicity. This study explored 2 adaptive strategies to mitigate this risk and proposes a new, automated method that minimizes replanning workload. Methods and Materials: Thirty patients with cervical cancer participated in a prospective clinical study and underwent pretreatment and weekly magnetic resonance (MR) scans over a 5-week course of daily external beam radiation therapy. Target volumes and organs at risk (OARs) were contoured on each of the scans. Deformable image registration was used to model the accumulated dose (the real dose delivered to the target and OARs) for 2 adaptive replanning scenarios that assumed a very small
Reprint requests to: Michael Milosevic, MD, FRCPC, Radiation Medicine Program, Princess Margaret Cancer Centre, 610 University Ave, Toronto, Ontario, Canada M5G 2M9. Tel: (416) 946-2932; E-mail: mike. [email protected] Portions of this study were presented at the 51st Annual Meeting of the American Society for Radiation Oncology, November 1-5, 2009, Chicago, IL. This work was supported by RaySearch Laboratories AB, the Canadian Institutes of Health Research Strategic Fellowship in the Excellence in Radiation Research for the 21st Century Program, the Giovanni and Concetta Guglietti Family Trust, the National Sciences and Engineering Int J Radiation Oncol Biol Phys, Vol. 90, No. 1, pp. 147e154, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.05.039
Research Council of Canada, and the Ontario Consortium for Adaptive Interventions in Radiation Oncology. Drs Lim and Stewart contributed equally to this work and share first authorship. Conflict of interest: Anna Lundin, Henrik Rehbinder, and Johan Lo¨f are employees and shareholders of RaySearch Laboratories AB. David Jaffray, Joanne Moseley, and Kristy Brock have a commercial licensing agreement with RaySearch Laboratories AB. The authors report no other conflicts of interest.
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margins, substantial interfractional motion, and tumor regression and deformation during treatment. This study highlights the dosimetric impact of this anatomic variability and proposes a new and practical adaptive strategy for assuring robust target coverage while minimizing programmatic workload.
PTV margin of only 3 mm to account for setup and internal interfractional motion: (1) a preprogrammed, anatomy-driven midtreatment replan (A-IMRT); and (2) a dosimetry-triggered replan driven by target dose accumulation over time (D-IMRT). Results: Across all 30 patients, clinically relevant target dose thresholds failed for 8 patients (27%) if 3-mm margins were used without replanning. A-IMRT failed in only 3 patients and also yielded an additional small reduction in OAR doses at the cost of 30 replans. D-IMRT assured adequate target coverage in all patients, with only 23 replans in 16 patients. Conclusions: A novel, dosimetry-triggered adaptive IMRT strategy for patients with cervical cancer can minimize the risk of target underdosing in the setting of very small margins and substantial interfractional motion while minimizing programmatic workload and cost. Ó 2014 Elsevier Inc.
Introduction Development of a clinically robust small-margin intensity modulated radiation therapy (IMRT) treatment approach to minimize normal tissue toxicities in cervical cancer is hampered by the highly variable and patient-specific nature of uterine motion (1, 2) combined with significant tumor regression and deformation during treatment (3, 4). The dosimetric consequences of these anatomical changes over a course of fractionated RT can result in target underdosing and higher-than-expected doses to adjacent normal tissue (5, 6). To accommodate these anatomic variations, most cervix IMRT protocols use planning target volume (PTV) margins of 1 to 3 cm (7). Margins of this magnitude detract from the therapeutic benefit of IMRT and limit the potential for dose escalation and normal tissue sparing. Translational shifts and other direct correction strategies to ensure target coverage may not be optimal in patients with cervical cancer due to the complex intrapelvic organ dynamics that occur during treatment. Proposed approaches to overcome this difficulty include margin reduction based on weekly magnetic resonance image (MRI)-guided replanning (8), automated replanning with soft tissue imaging and deformable dose accumulation (9), a combination of soft tissue matching and off-line replanning approaches (10), and “margin-of-the-day” strategies (11). Although such adaptive strategies reduce the risk of target underdosing, the workload associated with creating multiple plans per patient detracts from clinical feasibility. Moreover, in patients with limited anatomic motion and target regression, the dosimetric improvements provided by frequent replanning may be too modest to warrant the increased clinical effort (9). The goal of this study was to evaluate 2 methods of implementing adaptive RT for patients with cervical cancer. The first method was a midtreatment replanning scenario in which a single replan was created halfway through treatment for every patient in an effort to correct minor target underdosing and reduce normal tissue dose. The second method was based on selective replanning triggered by
dosimetrically-significant anatomical changes observed using MRI. In this manner, replans were created only for patients who would likely benefit, at the time during treatment when they would benefit the most. Both strategies were modeled with deformable dose accumulation techniques to gain a more accurate representation of the dosimetric impact of intrapelvic organ dynamics on these highly conformal techniques.
Methods and Materials Patient characteristics Thirty women with International Federation of Gynecology and Obstetrics stage IB to IVA biopsy-proven cervical cancer participated in this prospective, Research Ethics Board-approved study after giving informed written consent. All patients received 45 to 50 Gy of whole-pelvis external beam RT in 1.8- to 2-Gy fractions over 5 weeks, using a 4-field box or parallel-opposed field technique with concomitant weekly cisplatin chemotherapy. Patient and treatment characteristics were summarized in a previous publication (9).
Imaging and contour delineation Each patient had a pelvic computed tomography (CT) scan before treatment and MR scans before and weekly during external beam RT. Patients were imaged and treated in the supine position and complied with a departmental bladder and bowel preparation protocol (2). The MRI protocol consisted of axial T2-weighted fast spin echo images from the sacral promontory to the bottom of the obturator foramen, with patients set up on a standard diagnostic MR couch (2). Twelve of the 30 patients had 6 MR scans in total, and the remaining 18 had 5 scans. Each MRI was registered to the pretreatment CT scan by matching to pelvic bones. Targets and organs-at-risk (OARs) were then manually contoured on the pretreatment and weekly MR images by a single
Volume 90 Number 1 2014
Adaptive IMRT for cervical cancer
investigator before review and approval by a second investigator. Clinical target volumes (CTV) were separated into primary (pCTV) and nodal (nCTV) components, as defined in Table 1. The pCTV was based on a previous consensus definition (13), with the exception that only 2 cm of the uterus superior to the gross tumor volume (GTV) was included. This reflected local practice and was predicated on the availability of pretreatment MRI to provide robust determination of the extent of intrauterine involvement. Dose to nCTV was not assessed in this study; movement of the nodal volume along the pelvic sidewall was assumed to be small compared to that of the pCTV, and the nCTV was assumed to receive the prescribed dose. OARs were contoured as solid organs and included the bladder, rectum, sigmoid, and small bowel (contoured as a contiguous volume). The pCTV and OARs are shown in Figure 1 for a typical patient.
Radiation therapy treatment planning An IMRT plan was developed using specialized research software (ORBIT Workstation; RaySearch Laboratories AB, Stockholm, Sweden) (14) by a single experienced dosimetrist. Pre-treatment contours were used with a prescription dose of 50 Gy and a 3-mm isotropic PTV margin, which was felt to be at the extreme limit of practicality given contouring uncertainties, set up variation, and intrafractional motion (2). Planning objectives and OAR constraints were derived from Radiation Therapy Oncology Group study 0418 for postoperative IMRT of endometrial or cervical cancer and are summarized in Table 2. These OAR criteria, developed for the postoperative setting with small target volumes, could not be met in all patients. For such patients, OAR constraints were relaxed until target objectives were met. Step-and-shoot IMRT with 6-MV photons and 7 beam angles was used for all patients. Table 1 pCTV
The methodology for deformable registration and dose accumulation has been detailed previously (6, 9). The framework is outlined in Figure 2 in the context of the adaptive strategies discussed in the next section. First, each weekly MRI was associated with a specific fraction, assuming that the anatomy remained constant until the next scan. The pretreatment and weekly contours for the GTV, bladder, upper vagina, cervix, uterus, rectum-sigmoid, and pelvic bone were converted to 3-dimensional surface meshes. The MORFEUS deformable registration algorithm (15) was used to deform these fractional organ meshes back to their planning (or pretreatment) anatomical geometry, simultaneously transforming the dose (calculated on the planning CT) to its deformed fractional representation. Finally, the deformed fractional doses were accumulated over all fractions using ORBIT workstation (Fig. 2). The final accumulated dose distribution models the dosimetric impact of interfractional motion relative to the fractionated treatment. The accuracy of the MORFEUS deformation algorithm has previously been validated to a mean vector error of 0.22 0.09 cm for an imaging resolution of 0.2 cm (16).
Adaptive IMRT strategies Two adaptive IMRT strategies were investigated in this study: (1) anatomical adaptive IMRT (A-IMRT), an off-line midtreatment replan for each patient, using the anatomy from the MR scan closest to the midpoint of treatment. Replans were created using the same criteria as the initial plans by the same dosimetrist and applied for the remainder of treatment. The rationale for this strategy was to exploit pCTV regression to reduce dose to surrounding normal tissues while maintaining target coverage; and (2) Dosimetric adaptive IMRT (D-IMRT) is a replan that was triggered during treatment if
Component GTV GTV þ 7 mm Parametrium Cervix Uterus Vagina
nCTV
Deformable registration and dose accumulation
Target volume definitions
Target
Nodal volumes derived from corresponding vessels (12)
149
Definition Intermediate to high signal on T2-weighted MRI A 7-mm expansion of the GTV (excluding surrounding normal critical organs) Soft tissue adjacent to GTV/cervix/uterus compassed by the broad ligament Any remaining normal cervix 2 cm of uterus superior to the GTV (entire uterus included for 3 patients with less than 2 cm of healthy uterus above GTV) 2 cm of vagina inferior to the GTV Union of 1) internal and external lymph nodes; 2) common iliac lymph nodes; 3) presacral lymph nodes
Abbreviations: GTV Z gross tumor volume; nCTV Z nodal clinical target volume; pCTV Z primary clinical target volume.
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a
Fig. 1.
b
Primary tumor targets and normal tissue contours of 1 patient in transverse (a) and sagittal (b) orientations.
the final target dose was predicted to be low. After each MR scan, the end-of-treatment accumulated dose was estimated by using all available contoured MRI information to that point, and it was assumed that the patient anatomy remained constant for the remainder of treatment. An off-line replan was created for the following fraction if the estimated accumulated dose to 98% (D98) of the GTV or pCTV was below 98% (49 Gy) or 95% (47.5 Gy) of the prescription dose, respectively. Each triggered replan was automatically optimized using the pretreatment dose-volume histogram criteria (created by the dosimetrist for the initial treatment plan) and the most recent patient anatomy (from the contoured MR scan). The accumulated replanning strategies were compared to the accumulated no-replanning scenario, which used the initial plan throughout treatment. Differences were assessed using an unequal variance Student t test with a P value of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation
Dosimetrically Triggered Adaptive Intensity Modulated Radiation Therapy for Cervical Cancer Karen Lim, MBBS,* James Stewart, MASc,y,z Valerie Kelly, MSc,y,x Jason Xie, MSc,y Kristy K. Brock, PhD,jj Joanne Moseley, BMath,y Young-Bin Cho, PhD,y,x Anthony Fyles, MD,y,x Anna Lundin, MSc,{ Henrik Rehbinder, PhD,{ Johan Lo¨f, PhD,{ David A. Jaffray, PhD,y,z,x,#,** and Michael Milosevic, MDy,x *Department of Radiation Oncology, Liverpool Hospital, Sydney, Australia; yRadiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; z Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada; xDepartment of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; jj Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan; {RaySearch Laboratories AB, Stockholm, Sweden; #Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; and **Techna Institute for the Advancement of Technology for Health, Toronto, Ontario, Canada Received Mar 18, 2014, and in revised form May 16, 2014. Accepted for publication May 20, 2014.
Summary High-precision image guided radiation therapy has the potential to reduce treatment side effects in cervical cancer. However, uptake of intensity modulated radiation therapy has been limited because of target underdosing concerns in the setting of very narrow
Purpose: The widespread use of intensity modulated radiation therapy (IMRT) for cervical cancer has been limited by internal target and normal tissue motion. Such motion increases the risk of underdosing the target, especially as planning margins are reduced in an effort to reduce toxicity. This study explored 2 adaptive strategies to mitigate this risk and proposes a new, automated method that minimizes replanning workload. Methods and Materials: Thirty patients with cervical cancer participated in a prospective clinical study and underwent pretreatment and weekly magnetic resonance (MR) scans over a 5-week course of daily external beam radiation therapy. Target volumes and organs at risk (OARs) were contoured on each of the scans. Deformable image registration was used to model the accumulated dose (the real dose delivered to the target and OARs) for 2 adaptive replanning scenarios that assumed a very small
Reprint requests to: Michael Milosevic, MD, FRCPC, Radiation Medicine Program, Princess Margaret Cancer Centre, 610 University Ave, Toronto, Ontario, Canada M5G 2M9. Tel: (416) 946-2932; E-mail: mike. [email protected] Portions of this study were presented at the 51st Annual Meeting of the American Society for Radiation Oncology, November 1-5, 2009, Chicago, IL. This work was supported by RaySearch Laboratories AB, the Canadian Institutes of Health Research Strategic Fellowship in the Excellence in Radiation Research for the 21st Century Program, the Giovanni and Concetta Guglietti Family Trust, the National Sciences and Engineering Int J Radiation Oncol Biol Phys, Vol. 90, No. 1, pp. 147e154, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2014.05.039
Research Council of Canada, and the Ontario Consortium for Adaptive Interventions in Radiation Oncology. Drs Lim and Stewart contributed equally to this work and share first authorship. Conflict of interest: Anna Lundin, Henrik Rehbinder, and Johan Lo¨f are employees and shareholders of RaySearch Laboratories AB. David Jaffray, Joanne Moseley, and Kristy Brock have a commercial licensing agreement with RaySearch Laboratories AB. The authors report no other conflicts of interest.
148
International Journal of Radiation Oncology Biology Physics
Lim et al.
margins, substantial interfractional motion, and tumor regression and deformation during treatment. This study highlights the dosimetric impact of this anatomic variability and proposes a new and practical adaptive strategy for assuring robust target coverage while minimizing programmatic workload.
PTV margin of only 3 mm to account for setup and internal interfractional motion: (1) a preprogrammed, anatomy-driven midtreatment replan (A-IMRT); and (2) a dosimetry-triggered replan driven by target dose accumulation over time (D-IMRT). Results: Across all 30 patients, clinically relevant target dose thresholds failed for 8 patients (27%) if 3-mm margins were used without replanning. A-IMRT failed in only 3 patients and also yielded an additional small reduction in OAR doses at the cost of 30 replans. D-IMRT assured adequate target coverage in all patients, with only 23 replans in 16 patients. Conclusions: A novel, dosimetry-triggered adaptive IMRT strategy for patients with cervical cancer can minimize the risk of target underdosing in the setting of very small margins and substantial interfractional motion while minimizing programmatic workload and cost. Ó 2014 Elsevier Inc.
Introduction Development of a clinically robust small-margin intensity modulated radiation therapy (IMRT) treatment approach to minimize normal tissue toxicities in cervical cancer is hampered by the highly variable and patient-specific nature of uterine motion (1, 2) combined with significant tumor regression and deformation during treatment (3, 4). The dosimetric consequences of these anatomical changes over a course of fractionated RT can result in target underdosing and higher-than-expected doses to adjacent normal tissue (5, 6). To accommodate these anatomic variations, most cervix IMRT protocols use planning target volume (PTV) margins of 1 to 3 cm (7). Margins of this magnitude detract from the therapeutic benefit of IMRT and limit the potential for dose escalation and normal tissue sparing. Translational shifts and other direct correction strategies to ensure target coverage may not be optimal in patients with cervical cancer due to the complex intrapelvic organ dynamics that occur during treatment. Proposed approaches to overcome this difficulty include margin reduction based on weekly magnetic resonance image (MRI)-guided replanning (8), automated replanning with soft tissue imaging and deformable dose accumulation (9), a combination of soft tissue matching and off-line replanning approaches (10), and “margin-of-the-day” strategies (11). Although such adaptive strategies reduce the risk of target underdosing, the workload associated with creating multiple plans per patient detracts from clinical feasibility. Moreover, in patients with limited anatomic motion and target regression, the dosimetric improvements provided by frequent replanning may be too modest to warrant the increased clinical effort (9). The goal of this study was to evaluate 2 methods of implementing adaptive RT for patients with cervical cancer. The first method was a midtreatment replanning scenario in which a single replan was created halfway through treatment for every patient in an effort to correct minor target underdosing and reduce normal tissue dose. The second method was based on selective replanning triggered by
dosimetrically-significant anatomical changes observed using MRI. In this manner, replans were created only for patients who would likely benefit, at the time during treatment when they would benefit the most. Both strategies were modeled with deformable dose accumulation techniques to gain a more accurate representation of the dosimetric impact of intrapelvic organ dynamics on these highly conformal techniques.
Methods and Materials Patient characteristics Thirty women with International Federation of Gynecology and Obstetrics stage IB to IVA biopsy-proven cervical cancer participated in this prospective, Research Ethics Board-approved study after giving informed written consent. All patients received 45 to 50 Gy of whole-pelvis external beam RT in 1.8- to 2-Gy fractions over 5 weeks, using a 4-field box or parallel-opposed field technique with concomitant weekly cisplatin chemotherapy. Patient and treatment characteristics were summarized in a previous publication (9).
Imaging and contour delineation Each patient had a pelvic computed tomography (CT) scan before treatment and MR scans before and weekly during external beam RT. Patients were imaged and treated in the supine position and complied with a departmental bladder and bowel preparation protocol (2). The MRI protocol consisted of axial T2-weighted fast spin echo images from the sacral promontory to the bottom of the obturator foramen, with patients set up on a standard diagnostic MR couch (2). Twelve of the 30 patients had 6 MR scans in total, and the remaining 18 had 5 scans. Each MRI was registered to the pretreatment CT scan by matching to pelvic bones. Targets and organs-at-risk (OARs) were then manually contoured on the pretreatment and weekly MR images by a single
Volume 90 Number 1 2014
Adaptive IMRT for cervical cancer
investigator before review and approval by a second investigator. Clinical target volumes (CTV) were separated into primary (pCTV) and nodal (nCTV) components, as defined in Table 1. The pCTV was based on a previous consensus definition (13), with the exception that only 2 cm of the uterus superior to the gross tumor volume (GTV) was included. This reflected local practice and was predicated on the availability of pretreatment MRI to provide robust determination of the extent of intrauterine involvement. Dose to nCTV was not assessed in this study; movement of the nodal volume along the pelvic sidewall was assumed to be small compared to that of the pCTV, and the nCTV was assumed to receive the prescribed dose. OARs were contoured as solid organs and included the bladder, rectum, sigmoid, and small bowel (contoured as a contiguous volume). The pCTV and OARs are shown in Figure 1 for a typical patient.
Radiation therapy treatment planning An IMRT plan was developed using specialized research software (ORBIT Workstation; RaySearch Laboratories AB, Stockholm, Sweden) (14) by a single experienced dosimetrist. Pre-treatment contours were used with a prescription dose of 50 Gy and a 3-mm isotropic PTV margin, which was felt to be at the extreme limit of practicality given contouring uncertainties, set up variation, and intrafractional motion (2). Planning objectives and OAR constraints were derived from Radiation Therapy Oncology Group study 0418 for postoperative IMRT of endometrial or cervical cancer and are summarized in Table 2. These OAR criteria, developed for the postoperative setting with small target volumes, could not be met in all patients. For such patients, OAR constraints were relaxed until target objectives were met. Step-and-shoot IMRT with 6-MV photons and 7 beam angles was used for all patients. Table 1 pCTV
The methodology for deformable registration and dose accumulation has been detailed previously (6, 9). The framework is outlined in Figure 2 in the context of the adaptive strategies discussed in the next section. First, each weekly MRI was associated with a specific fraction, assuming that the anatomy remained constant until the next scan. The pretreatment and weekly contours for the GTV, bladder, upper vagina, cervix, uterus, rectum-sigmoid, and pelvic bone were converted to 3-dimensional surface meshes. The MORFEUS deformable registration algorithm (15) was used to deform these fractional organ meshes back to their planning (or pretreatment) anatomical geometry, simultaneously transforming the dose (calculated on the planning CT) to its deformed fractional representation. Finally, the deformed fractional doses were accumulated over all fractions using ORBIT workstation (Fig. 2). The final accumulated dose distribution models the dosimetric impact of interfractional motion relative to the fractionated treatment. The accuracy of the MORFEUS deformation algorithm has previously been validated to a mean vector error of 0.22 0.09 cm for an imaging resolution of 0.2 cm (16).
Adaptive IMRT strategies Two adaptive IMRT strategies were investigated in this study: (1) anatomical adaptive IMRT (A-IMRT), an off-line midtreatment replan for each patient, using the anatomy from the MR scan closest to the midpoint of treatment. Replans were created using the same criteria as the initial plans by the same dosimetrist and applied for the remainder of treatment. The rationale for this strategy was to exploit pCTV regression to reduce dose to surrounding normal tissues while maintaining target coverage; and (2) Dosimetric adaptive IMRT (D-IMRT) is a replan that was triggered during treatment if
Component GTV GTV þ 7 mm Parametrium Cervix Uterus Vagina
nCTV
Deformable registration and dose accumulation
Target volume definitions
Target
Nodal volumes derived from corresponding vessels (12)
149
Definition Intermediate to high signal on T2-weighted MRI A 7-mm expansion of the GTV (excluding surrounding normal critical organs) Soft tissue adjacent to GTV/cervix/uterus compassed by the broad ligament Any remaining normal cervix 2 cm of uterus superior to the GTV (entire uterus included for 3 patients with less than 2 cm of healthy uterus above GTV) 2 cm of vagina inferior to the GTV Union of 1) internal and external lymph nodes; 2) common iliac lymph nodes; 3) presacral lymph nodes
Abbreviations: GTV Z gross tumor volume; nCTV Z nodal clinical target volume; pCTV Z primary clinical target volume.
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a
Fig. 1.
b
Primary tumor targets and normal tissue contours of 1 patient in transverse (a) and sagittal (b) orientations.
the final target dose was predicted to be low. After each MR scan, the end-of-treatment accumulated dose was estimated by using all available contoured MRI information to that point, and it was assumed that the patient anatomy remained constant for the remainder of treatment. An off-line replan was created for the following fraction if the estimated accumulated dose to 98% (D98) of the GTV or pCTV was below 98% (49 Gy) or 95% (47.5 Gy) of the prescription dose, respectively. Each triggered replan was automatically optimized using the pretreatment dose-volume histogram criteria (created by the dosimetrist for the initial treatment plan) and the most recent patient anatomy (from the contoured MR scan). The accumulated replanning strategies were compared to the accumulated no-replanning scenario, which used the initial plan throughout treatment. Differences were assessed using an unequal variance Student t test with a P value of
