Intrafraction Prostate Motion Management for Ultra-Hypofractionated Radiotherapy of Prostate Cancer
and Uwe Schneider 2,‡
Round 1
Reviewer 1 Report
The topic is worthy of interest and few literature data are currently available.
Overall, I found some passages of the article not completely clear.
1) Introduction:
First, the use of intra-prostatic radiopaque fiducial markers is proper to the CyberKnife while ultra-hypofractionated prostate irradiation may be also Linac-based, hence with image guidance different from fiducial tracking, as you mentioned in the previous paragraph.
Second, VMAT, IMRT and FFF are not three different radiotherapy techniques. VMAT technique is a type of IMRT, volumetric IMRT, and FFF is a VMAT mode that allows to perform stereotactic treatment plans
The introduction should be rewritten to better fit with the content of the study.
Line 74-78: details on the analyzed radiation technique may be added to better introduce the focus of the study on intra-fraction translational prostate displacement for tracking decision.
2) Materials and methods
Line 85: what does CLINACS mean? Did you mean LINAC? Cyberknife Linac? I could not find the explanation of such abbreviation in any section of the article.
Line 85-86: did you required comfortable bladder filling? What about empty rectum? Did the recruited patients undergo enema before the treatment procedures?
3) Discussion
Line 191: what does CLINACS mean? (see Materials and methods)
Line 202: the same as Introduction
Line 256: FFF is not a radiation technique by itself. “..using the FFF mode” may be more appropriate.
Line 288: what did you exactly mean by “reimaging” and “repositioning” before adaptive RT? More and clearer details about should be added.
4) Conclusions
I found the sentences a bit confusing as they were written.
A clearer version might be the following: “Intra-fraction motion management is recommended for ultra-hypofractionated RT of the prostate with treatment times above 2.5 minutes, including monitoring and correction since prostate dislocations are unacceptably high. An intra-fraction imaging interval of <50 sec allows PTV safety margins for intra-fraction uncertainties between 0.5 – 1 mm. Intra-fraction prostate motion is low for treatment times below 2.5 minutes, and may be reasonably compensated by additional PTV margin of 2-3 mm. Reimaging and repositioning may be recommended for extremely prolonged treatment duration as with AI and MR-based ART.
Finally, the English need to be revised for the entire manuscript.
Author Response
Comments and Suggestions for Authors
The topic is worthy of interest and few literature data are currently available.
Overall, I found some passages of the article not completely clear.
1) Introduction:
First, the use of intra-prostatic radiopaque fiducial markers is proper to the CyberKnife while ultra-hypofractionated prostate irradiation may be also Linac-based, hence with image guidance different from fiducial tracking, as you mentioned in the previous paragraph.
Answer: Line 68-72: The sentence has been adapted: Various techniques have been proposed for prostate motion monitoring and compensation, including intra-prostatic radiopaque fiducial markers (FM) with in-room imaging, ultrasound-based systems, electromagnetic tracking, and MRI systems integrated into the treatment room, all of which are suitable for LINACs [10]. For Cyberknife treatment, the use of intra-prostatic radiopaque FM is required.
Second, VMAT, IMRT and FFF are not three different radiotherapy techniques. VMAT technique is a type of IMRT, volumetric IMRT, and FFF is a VMAT mode that allows to perform stereotactic treatment plans
Answer: Line 54-57: The sentence has been adapted: Treatment duration may vary substantially from 1 min to more than 10 min and depends not only on the fractionation scheme but also on the treatment machine (linear accelerator (LINAC) vs. Cyberknife) or beam modulation (flattening-filter free (FFF) vs. flattening filter) [3, 4].
The introduction should be rewritten to better fit with the content of the study.
Answer: Line 47-83: The introduction has been rewritten and two references have been added:
Prostate cancer is the most common cancer in men, with an incidence of 113/100,000 men per year [1]. Radiotherapy (RT) is one of the main curative treatment modalities besides surgery. Recently, ultra-hypofractionated radiotherapy has been proven to be non-inferior to conventionally fractionated radiotherapy, and it has been increasingly applied since [2].
The use of ultra-hypofractionated radiotherapy leads to prolonged treatment times compared with normal fractionated and moderately hypofractionated RT. Treatment duration may vary substantially from 1 min to more than 10 min and depends not only on the fractionation scheme but also on the treatment machine (linear accelerator (LINAC) vs. Cyberknife) or beam modulation (flattening-filter free (FFF) vs. flattening filter) [3, 4].
Treatment duration plays a crucial role in the amount of intra-fraction prostate motion [3, 5]. Prolonged treatment times of 10 min compared with 5 min lead to increased prostate shifts by 3 mm and more [6-8]. Consecutively, prolonged treatment times harbor the risk of geographical miss and demand either the adoption of larger planned target volume (PTV) margins at the cost of normal tissue exposure and toxicity or intra-fractional tracking/monitoring. For moderately hypofractionated RT, intra-fractional prostate motion is usually compensated for with the adaptation of the PTV margin [9]. On the other hand, for stereotactic and ultra-hypofractionated RT, prostate tracking/monitoring is the preferred method. Currently, it is not clear which treatment times demand intra-fraction prostate motion tracking rather than compensation with safety margins.
Various techniques have been proposed for prostate motion monitoring and compensation, including intra-prostatic radiopaque fiducial markers (FM) with in-room imaging, ultrasound-based systems, electromagnetic tracking, and MRI systems integrated into the treatment room, all of which are suitable for LINACs [10]. For Cyberknife treatment, the use of intra-prostatic radiopaque FM is required. Radiopaque markers require repetitive intra-fractional imaging. Some institutions investigated an imaging interval of 40 sec [7] or 60-180 seconds [6], while others suggested an imaging frequency depending on margin size, i.e., every 15, 60, or 240 seconds for 1 mm, 2 mm, or 3 mm margins, respectively [11]. Currently, there are no guidelines on what imaging frequency should be used.
This study aimed to use intra-prostatic radiopaque FM tracking by repetitive in-room imaging in order 1) to evaluate the time-dependent magnitude of intra-fraction translational prostate displacement, 2) to determine an optimal intra-fractional imaging frequency allowing minimal margins, and 3) to determine a time cutoff for decision making of compensation modality, i.e., PTV margins compensation vs. intra-fraction prostate tracking.
Line 74-78: details on the analyzed radiation technique may be added to better introduce the focus of the study on intra-fraction translational prostate displacement for tracking decision.
Answer: Line 78-83: The aim paragraph has been adapted: The aim of this study was to use intra-prostatic radiopaque FM tracking by repetitive in-room imaging in order 1) to evaluate the time-dependent magnitude of intra-fraction translational prostate displacement, 2) to determine an optimal intra-fractional imaging frequency allowing minimal margins and 3) to determine a time-cutoff for decision making of compensation modality, i.e. PTV margins compensation vs. intra-fraction prostate tracking.
2) Materials and methods
Line 85: what does CLINACS mean? Did you mean LINAC? Cyberknife Linac? I could not find the explanation of such abbreviation in any section of the article.
Answer: Line 90: The word CLINAC has been changed to LINAC
Line 85-86: did you required comfortable bladder filling? What about empty rectum? Did the recruited patients undergo enema before the treatment procedures?
Answer: Line 90-92: The sentence has been adapted: patients were treated in supine position with comfortable bladder filling and emptied rectum using laxatives but without endorectal balloon (ERB).
3) Discussion
Line 191: what does CLINACS mean? (see Materials and methods)
Answer: Line 196 / 206 / 2018: The word CLINACS has been changed to LINAC’s
Line 202: the same as Introduction
Answer: Line 205-207: the sentence has been adapted: The duration of radiotherapy may vary substantially from 1 min to more than 10 min depending on the fractionation scheme, treatment machine (Cyberknife vs. LINAC), and beam modulation (FFF vs. flattening filter) [3, 4].
Line 256: FFF is not a radiation technique by itself. “..using the FFF mode” may be more appropriate.
Answer: Line 261: The sentence has been adapted: Treatment time for SBRT can significantly be reduced by using the FFF mode [27].
Line 288: what did you exactly mean by “reimaging” and “repositioning” before adaptive RT? More and clearer details about should be added.
Answer: Line 284-287: The sentence has been adapted: Hence, MR or CBCT (cone-beam computed tomography) reimaging and target realignment before the start of the actual treatment is reasonable, irrespective of the intra-fractional compensation method.
4) Conclusions
I found the sentences a bit confusing as they were written.
A clearer version might be the following: “Intra-fraction motion management is recommended for ultra-hypofractionated RT of the prostate with treatment times above 2.5 minutes, including monitoring and correction since prostate dislocations are unacceptably high. An intra-fraction imaging interval of <50 sec allows PTV safety margins for intra-fraction uncertainties between 0.5 – 1 mm. Intra-fraction prostate motion is low for treatment times below 2.5 minutes, and may be reasonably compensated by additional PTV margin of 2-3 mm. Reimaging and repositioning may be recommended for extremely prolonged treatment duration as with AI and MR-based ART.
Answer: Line 289-296: The conclusion paragraph has been adopted as suggested.
Intra-fraction motion management is recommended for ultra-hypofractionated RT of the prostate with treatment times above 2.5 minutes, including monitoring and correction since prostate dislocations are unacceptably high. An intra-fraction imaging interval of <50 sec allows PTV safety margins for intra-fraction uncertainties between 0.5 and 1 mm. Intra-fraction prostate motion is low for treatment times below 2.5 minutes and may be reasonably compensated by an additional PTV margin of 2-3 mm. Reimaging and target realignment may be recommended for extremely prolonged treatment durations, as with AI- and MR-based ART.
Finally, the English need to be revised for the entire manuscript.
Answer: The paper has undergone English language editing by MDPI.
Author Response File: 
Author Response.docx
Reviewer 2 Report
Authors should be congratulated for the great work. The topic is interesting and challenging. The role of Ultra-hypofractionated radiotherapy for prostate cancer is growing and with it the need for new systems to minimize the risks for patients, while not giving up the benefits of the technique. The manuscript is well-written and easily readable, the methodology is robust, figures and tables are clear. The manuscript is suitable for publication.
Author Response
Comments and Suggestions for Authors:
Authors should be congratulated for the great work. The topic is interesting and challenging. The role of Ultra-hypofractionated radiotherapy for prostate cancer is growing and with it the need for new systems to minimize the risks for patients, while not giving up the benefits of the technique. The manuscript is well-written and easily readable, the methodology is robust, figures and tables are clear. The manuscript is suitable for publication.
Answer: We thank the reviewer for the favorable comments.
Author Response File: Author Response.docx
