Table 2: Public Reviewer Comments

Disposition of Comments

Comments received from draft review on Radiation Therapy for Localized Prostate Cancer: an Update.

Radiation Therapy for Localized Prostate Cancer

Disposition of Comments

Project ID: CANT1209

Table 2: Public Review Comments

Reviewer Name1Reviewer Affiliation2Section3Reviewer CommentsAuthor Response4

Anonymous Reviewer 1

American Society for Radiation Oncology (ASROGeneral

ASRO, the largest radiation oncology society in the world with 10,000 members who specialize in treating patients with radiation therapies, appreciates the opportunity to comment on the draft report: “Radiation Therapy for Localized Prostate Cancer: an Update.” In many respects, we think this report is well done. However, we have significant concerns about the decision to limit the review to T1-T2 disease with the primary key question focused on survival with radiation therapy compared to no treatment or no initial treatment. This doesn’t seem like a good criterion to filter out articles that might illustrate the basic issue at hand: does RT provide benefit to patients?

We appreciate the indolent nature of many prostate cancers and ASTRO members routinely counsel patients that active surveillance or watchful waiting may be the appropriate management for their disease. Yet, there is no well defined criterion that defines active surveillance or how patients should be managed if they select active management. Given that the role for active surveillance in 2010 remains controversial, ASTRO believes it is unreasonable to expect that this review would address the value of radiation relative to active surveillance looking at survival. To do so would imply that active surveillance was a legitimate option 10-20 years ago and that phase II studies could have reasonably been conducted. Even today, accrual to such a study would be limited by patient preference.

We also agree with the statement, “Because of the differential survival rates based on tumor grade, there has been an increased focus on identifying and treating patients with aggressive subtypes whose overall survival is likely to be impacted by their cancer, while deferring treatment for patients with indolent subtypes and/or short life-expectancy, whose overall survival is not likely to be impacted by their cancer” (page 2). At the same time, we consider it a major shortcoming of this report that T3 disease was excluded, as there are T3 patients with localized disease that have been proven to benefit from radiation therapy.

In particular, the focus on T1-T2 prostate cancer (and no consideration of T3 disease) precludes considering strong evidence of the role that radiotherapy plays in the curative treatment of prostate cancer. A seminal paper published by Widmark et al in 2009 (Lancet 2009; 373:301-308) demonstrated that radiotherapy improved survival in men with locally advanced disease. This study shows an overall survival benefit associated with radiation therapy. Further, it is important to note that 20% of the patients in this study had T1-T2 tumors. We have serious concerns that this study was excluded, particularly since it shows survival benefit, including the T1-T2 subset group.

The authors don’t discuss why there are so few trials comparing radiation therapy to watchful waiting. ASTRO believes it is incredibly hard to conduct a clinical trial in which treatment is compared to surveillance for any cancer. For example, there have been no U.S. trials of surgery compared to watchful waiting that have been reported. We think that larger cultural issues are at play, and that broad outreach and education is needed so that patients can better understand their risks. Additionally, more biomarker research is needed so that patients with underlying risk of prostate cancer progression can be identified. Until such identification is reliable, some may question the ethics of a non-treatment arm of a possible study.

Thank you for your comment.

Our report is an update of a previous AHRQ sponsored comparative effectiveness review; that report restricts to studies on patients with T1 or T2 disease. Given that vast majority of patients diagnosed today have clinically localized disease, and not locally advanced disease, our review of patients with T1-T2 disease provides valuable information about radiation therapy for these patients.

We had a lengthy discussion on the trial by Widmark et al. Even though this trial is phase III prospective randomized data, it didn’t meet more than one of our inclusion criteria.
I) Treatments compared didn’t meet our inclusion criteria (looking only at direct comparative studies) to be included under any of our key questions.
II) This trial had all patients treated with hormone therapy.
III) This trial had included only 21% patients with T1/T2 disease.
IV) The analogy of A+B vs. B → A vs. nothing is an inference and not direct evidence.

A discussion regarding the small number of trials comparing radiation therapy and watchful waiting has been added to the report.

Anonymous Reviewer 1

American Society for Radiation Oncology (ASRO)Executive summary

We have identified a few issues and highlighted the discussion in the executive summary; we would note that these issues should be addressed where they appear in the report.

“EBRT administered as a standard fractionation or moderate hypofractionation does not seem to differ with respect to biochemical control and late genitourinary and gastrointestinal toxicities.” (page ES-7) We believe that if the terms “standard fractionation” and “moderate hypofractionation” are going to be used in this report, they should be specified. We would anticipate that by “standard fractionation,” the authors mean 1.8-2.0 Gy per fraction. However, we are unclear what is meant by the term “moderate hypofractionation” (e.g., >2.5 Gy per fraction? > 3 Gy per fraction? OR “ 19 fractions” “5 fractions?). Similarly, we believe the total dose to which these conclusions apply should also be stated to avoid confusion with alternative dose-fractionation regimens that are not studied in this report.

ASTRO is concerned that the report references recent New York Times stories, including a link to these stories (page ES-6), which report on very limited safety issues and implies that the quality assurance of radiation therapy may be insufficient. Patient safety is a comprehensive issue that is germane to all elements of a radiation oncology practice and is not limited to patients with prostate cancer. ASTRO has recently launched a “Target Safely” campaign to consolidate our efforts to enhance patient safety (http://www.astro.org/TargetSafely/). Further, radiation oncology literature is full of high quality publications about patient safety, machine safety, and quality assurance. However, none of the search terms for the literature review include quality assurance terms. ASTRO is deeply committed to the delivery of high quality care, but we believe this issue is outside the scope of this updated report. We believe the references to quality assurance and the New York Times articles should be removed, as their inclusion seems both outside the scope of the report and the references are prejudicial in nature.

“There were also no comparisons between EBRT and HDRBT.” (pg ES-4). While there are no randomized trials comparing EBRT to HDRBT monotherapy, there is one published randomized trial during the January 1 2007 - December 2009 timeframe. In this study, an HDRBT boost was compared to EBRT (Hoskin, Radiother Oncol 2007; 84:114-120). While small and with an unconventional EBRT dose, this study shows that the BT boost arm is superior without an increase in toxicity.

We find the following statements inconsistent: “Two studies did and two studies did not show that LDRBT was associated with significantly more genitourinary toxicity than EBRT.” (page ES-4) ?Available data also suggest that BT is associated with more genitourinary toxicity and less gastrointestinal toxicity compared with EBRT.? (page ES-7) Since the cited studies in the first statement have contradictory findings, ASTRO believes the later statement should be deleted or revised to state that there are similar toxicities between EBRT and BT.

Thank you for your request for clarification regarding the definition of standard fractionation and moderate hypofractionation. We had added the definition of “standard fractionation” in the final report.

We have adopted your suggestion regarding the reference to New York Times article and deleted it. Nevertheless, a lack of reporting on adverse event(s) with respect to quality assurance of radiation delivery was observed in the studies reviewed.

The publication by Hoskin et al. was excluded because less than 80% of participants had T1-T2 prostate cancer, and therefore did not meet our inclusion criteria.

Thank you for comment regarding the inconsistency with respect to the comparison between LDRBT and EBRT in the executive summary. The sentence has been modified after taking into consideration your suggestion.

Anonymous Reviewer 1

American Society for Radiation Oncology (ASRO)Methods

Again, we highlight our concern that the 2009 Widmark et al study was not included in this update and view its absence to be a major shortcoming of this report. While this study does include androgen deprivation therapy, it also includes data about the use of EBRT and therefore should have been included.

Based on the statement, “All abstracts concerning technical aspects of radiation therapy were re-screened by a radiation oncologist,” (page 9) it is unclear if radiation oncologists were involved in the literature review process and note that only one of the authors is a radiation oncologist. We believe inclusion of more specialists familiar with the topic is appropriate and would welcome the opportunity to work with AHRQ and its contractors in the future to identify recognized experts who might participate in literature reviews and drafting, lending expertise and insight that would likely be beneficial.

We question why the authors rated the multiple phase III dose trials as “moderate” evidence. These are high quality randomized trials that show a biochemical control benefit with higher doses of RT yet the authors of the review consider this to be only “moderate” evidence. We believe that the grading of evidence for these dose trials should be reconsidered.

We had a lengthy discussion on the trial by Widmark et al. Even though this trial is phase III prospective randomized data, it didn’t meet more than one of our inclusion criteria.
I) Treatments compared didn’t meet our inclusion criteria (looking only at direct comparative studies) to be included under any of our key questions.
II) This trial had all patients treated with hormone therapy.
III) This trial had included only 21% patients with T1/T2 disease.
IV) The analogy of A+B vs. B → A vs. nothing is an inference and not direct evidence.

Thank you for your suggestion about including more specialists in the development of this report. We will pass it on to AHRQ.

The criteria for rating the strength of evidence is described in the method section of the report.

Anita McGlothlinAmerican College of Radiology (ACR)GeneralThe American College of Radiology (ACR), representing over 32,000 diagnostic radiologists, radiation oncologists, medical physicists, interventional radiologists, and nuclear medicine physicians appreciate this opportunity to submit comments on the draft report titled “Radiation Therapy for Localized Prostate Cancer: An Update”, draft project ID CANT1209. The ACR fully endorses the American Society for Radiation Oncology (ASTRO) recommendations. Please refer to the ASTRO comments for the various aspects of the draft technology assessment report.Thank you for your comment.
Sonja Schoeppel, MDBaptist Regional Cancer CenterGeneral

I have been treating patients with prostate cancer since 1986. This was before PSA found cancers earlier. Back then, most patients seen had metastatic prostate cancer. With the advent of finding patients with earlier disease and more effective local treatment with radiation (implants and EBRT with IMRT) it is uncommon for me to see men with prostate cancer which has spread outside of the prostate and metastasized to bone. Dying of cancer in the bones is painful.

I have no doubt that finding prostate cancer earlier and eradicating it with radiation treatment prevents many men from dying of prostate cancer.

Thank you for your comment.
Todd R Wasserman, MDWashington University in St LouisGeneral

The data do not establish that RT in any form is better than no initial therapy, because the comparable data does not exist yet. The report does not state that the same lack of data does not prove the null hypothesis, that RT is only as good as no initial therapy.

The report concludes that EBRT dose escalation leads to better biochemical control. Teleologically, this is likely to be true because EBRT is of benefit with a lack of comparative data yet

Thank you for your comment.
Linda Winger, MSc, FACHEGeorgetown University Medical CenterGeneral

The CyberKnife® Coalition (CKC) congratulates the Agency on this thorough draft Technology Assessment, and welcome the opportunity to comment. In general we find it an excellent summary.

Formed in 2003 and incorporated in 2005, the CKC is a non-profit association of CyberKnife® user institutions, dedicated to protecting patients? access to this life-saving technology by working to ensure accurate and adequate reimbursement through educational, payer, and government advocacy. With a large body of academic support, the CyberKnife has now treated more than 80,000 patients worldwide and been installed as a radiosurgery system of choice by more than 190 institutions globally and 117 in the United States and Puerto Rico, many of whom are members of our Coalition.

There is, however, a crucial omission, for which we will provide specific comments, in the 'Introduction/Background' section related to the currently unique ability of CyberKnife to automatically compensate for movement of the target: the radiation beam moves with the tumor. We are sure that AHRQ representatives will have noted that clinicians who spoke in both the formal presentation, and public segment, of the meeting emphasized this point. It is critically important from a patient perspective, because it has obvious advantages in assuring that the prostate receives the planned dose and limiting collateral damage to healthy tissue.

Given the importance of this issue, and the status of AHRQ, we would encourage the Agency either to meet with us, or to visit a CyberKnife center at a time and location of the Agency’s choosing.

Thank you for your comment. In response to peer review comments, the use of the trade name Cyberknife® has been replaced with a standard definition -stereotactic body radiotherapy delivered in one or few fractions.
Linda Winger, MSc, FACHEGeorgetown University Medical CenterExecutive summaryPage ES-2 indicates “the intervention of interest was radiation treatment used as a first line treatment of prostate cancer.” We note this sentence in particular since all forms of radiation therapy with the exception of proton therapy have data/literature that supports sole mode of delivery treatment for localized prostate cancer. All of the literature contained within the technology assessment for proton therapy is for proton therapy as a boost to photon-based treatment. We therefore recommend that the technology assessment be modified to reflect the lack of sole mode delivery data for proton therapy. A potential update could reflect the following: “all technologies except proton therapy were used as the sole mode of radiation delivery; proton therapy was used as a boost to photon-based treatment.”Thank you for your comment about proton therapy. We did not find any comparative studies between proton and photon therapy as the definitive (rather than boost) treatment. For the purposes of this review, proton therapy delivered using conventional fractionation was considered to be external beam radiation therapy, because single institution series with conventional fractionation, a large number of patients (>500), and relatively long median follow up (>5 years) have been published, detailing the use of proton therapy as a definitive modality (Slater JD, Int J Radiat Oncol Biol Phys. 2004 Jun 1;59(2):348-52.)
Linda Winger, MSc, FACHEGeorgetown University Medical CenterIntroduction/ background

1. Page 4 indicates that two approaches are currently utilized to deal with the issue of intra-fraction motion “Calypso and CyberKnife. For the CyberKnife, the technology assessment indicates that ?implanted fiducial markers that are tracked prior to each treatment beam every few seconds.” Xie 2008 (Xie Y, et al. ?Intrafractional motion of the prostate during hypofractionated radiotherapy.? Int J Radiat Oncol Biol Phys 2008;72:236-246) indicates the following regarding the importance of utilizing the CyberKnife to TRACK PROSTATE MOTION AND TO AUTOMATICALLY CORRECT THE AIM OF THE TREATMENT BEAM WHEN PROSTATE MOVEMENT IS DETECTED? Our study shows the importance of real-time image guidance and motion-compensation techniques such as the robotic linear accelerator used in CyberKnife during hypofractionated prostate radiation treatment. Given the magnitude and random nature of prostate motion as well as recent technical advancements in various related fields, real-time monitoring of prostate position to compensate for the motion should be part of future prostate radiation therapy to ensure adequate dose coverage of the target while maintaining adequate sparing of adjacent structures.?

The central technological benefit of the CyberKnife System since its first clinical use in 1994 has been to use its image-guidance system to determine the location of the target, detect any target movement, and automatically correct the aim of the treatment beam. As Murphy put it in 2000 (Murphy MJ, et al. ?Image-Guided Radiosurgery for the Spine and Pancreas. Computer Aided Surgery 2000;5:278-288.), ?During each treatment, the image guidance system monitored the position of the target site and relayed the target coordinates to the beam-pointing system at discrete intervals. The pointing system then dynamically aligned the therapy beam with the lesion, automatically compensating for shifts in target position.?

This unique ability of the CyberKnife System, to detect prostate motion and automatically correct the beam aim to assure accurate radiation delivery, gives clinicians confidence that they are delivering high-dose radiation precisely to the prostate and not to surrounding tissues. We strongly request that the technology assessment be updated to reflect the ability of CyberKnife to utilize real-time image guidance to automatically compensate for shifts in target position.

2. Page 5 indicates that “incorporation of various body immobilization systems into IMRT with IGRT, together with increased daily dose, and limiting the number of treatments to at most 5, is known as stereotactic body radiation therapy.” However, the technology assessment fails to point out the differences between the many different treatment options considered SBRT. Martin and Gaya (Martin A, Gaya A. ?Stereotactic Body Radiotherapy: A Review.? Clinical Oncology 2010, doi:10.1016/j.clon.2009.12.003) indicated that a number of modern linacs with on-board imaging capabilities meet the basic image-guidance requirements for SBRT delivery, e.g. Varian Trilogy and Elekta Synergy. More recently there has been the introduction of linacs fully adapted as integrated stereotactic delivery systems. These include the Novalis TX, BrainLAB, Elekta Axesse, TomoTherapy Hi-Art System, and CyberKnife. Sahgal 2008 (Sahgal A, et al. ?Stereotactic Body Radiosurgery for Spinal Metastases: A Critical Review. Int J Radiat Oncol Biol Phys 2008;71:652-665) provides details regarding the differences between the SBRT systems. The article indicates that the CyberKnife and Novalis systems are equipped with in-room stereoscopic kilovoltage (kV) X-ray imaging. However, the article goes on to state that the CyberKnife is unique in that it uses intrafractional X-ray imaging (typically obtained every 30-60 s), and automatic LINAC position adjustments to compensate for any detected changes in target positioning.

We request that the technology assessment be updated to reflect two key differences between CyberKnife and other SBRT technologies: (1) no stereotactic immobilization is necessary with CyberKnife; and (2) CyberKnife is the only technology that automatically compensates for target movement throughout treatment, thereby keeping the radiation beams on target.

3. Page 5 indicates that ?despite the technical advances in delivery of external beam radiation, it may not be possible to deliver sufficiently high dose without incurring unacceptable normal tissue toxicity.? Several CyberKnife publications point to the contrary; these publications indicate that CyberKnife toxicity is equal to or better than other external beam radiation treatment options in avoiding normal tissue toxicity. For example, King et al. (King CR, et al. ?Stereotactic body radiotherapy for localized prostate cancer: interim results of a prospective phase II clinical trial.? Int J Radiat Oncol Biol Phys 2009;73:1043-1048) concluded based on a median 33-month follow-up that ?the outcomes from the clinical trial demonstrate that a hypofractionated course of stereotactic radiotherapy for localized prostate cancer is associated with urinary and rectal toxicity that are of the expected nature and severity as those experienced with conventionally fractionated courses of external beam radiotherapy.?

In addition, Katz et al. (Katz AJ, et al. ?Stereotactic body radiation therapy for organ confined prostate cancer.? BMC Urology. 2010:10:1) noted based on a median 30-month follow-up that ??although our therapeutic doses were higher than [several reviewed IMRT] studies our observed rate of acute urinary and rectal toxicity was lower, with less than 5% of patients experiencing any Grade II urinary or rectal toxicity and none experiencing any higher grade acute toxicity.? Friedland et al. (Friedland J et al. ?Stereotactic body radiotherapy: an emerging treatment approach for localized prostate cancer.? Technol Cancer Res Treat 2009;8:387-392.) also reported very low rates of toxicity at a median of 2 years.

The literature supports the proposition that the very precise targeting will limit collateral damage to healthy tissue to well within acceptable levels while high radiation doses are delivered to the prostate. We therefore contest the suggestion that ?it may not be possible to deliver sufficiently high dose without incurring unacceptable normal tissue toxicity?, and request that this language should be moderated.

Thank you for your detailed information about the Cyberknife® system. Based on our search criteria, we did not find any comparative studies between Cyberknife® and other radiation therapy delivery systems that reported clinical outcomes.

Thank you for your comment about the different types of SBRT systems. Based on our search criteria, we did not find any comparative studies between Cyberknife® and other radiation therapy delivery systems that reported clinical outcomes.

Thank you for your comment about possible reduction in adverse events with Cyberknife®. Based on our search criteria, we did not find any comparative studies between Cyberknife® and other radiation therapy delivery systems that reported clinical outcomes including rates of adverse events.

Linda Winger, MSc, FACHEGeorgetown University Medical CenterDiscussion/Conclusion

1. The section labeled ?Future Research? indicates that ?randomized trials to address the question of extremely hypofractionated (SBRT or HDRBT) radiation therapy should be conducted.? However, we are sure that the Agency will have noted two key comments made by the MEDCAC panel at the April 21, 2010 MEDCAC (Radiation Therapy for Localized Prostate Cancer) meeting. First, the panel recognized that randomized clinical trials or observational studies are necessary for ALL forms of radiation therapy for localized prostate cancer, rather than limiting this comment to extremely hypofractionated (SBRT or HDRBT) radiation therapy. Second, the panel discussed that, while randomized controlled trials (RCTs) are desirable, there are practical difficulties associated with them which, together with a rate of innovation that renders a technology obsolete by the time the RCT conclusions are known. The MEDCAC suggested that registries may be a more practical solution.

Given the panel?s comments at the MEDCAC meeting (which will be publically available), we request that the sentence be changed to note that ?randomized clinical trials, retrospective studies, or observational studies including registries should be used in order to address all types of radiation therapy for localized prostate cancer.?

2. The section labeled ?Future Research? indicates, ?our current review did not identify any comparative studies evaluating the role of particle radiation therapy (e.g., proton) in the treatment of prostate cancer. Data from such studies will help decide how to best use these limited resources.? Given the fact that there are no publications for proton therapy as the sole mode of radiation delivery (proton therapy was used as a boost to photon-based treatment), we request that the ?Future Research? sentence be changed to reflect the lack of sole mode proton therapy data. We request the sentence read, ?Our current review did not identify any comparative studies evaluating the role of particle radiation therapy (e.g., proton) as a sole mode delivery in the treatment of prostate cancer. Data from future studies may highlight proton therapy as a sole mode of radiation delivery for prostate cancer will help decide how to best use these limited resources.?

Your comment on study designs other than RCT is appreciated. We did include comparative study designs other than randomized trials in our review of the literature. In fact, the large majority of included studies were not randomized trials, and registry-based studies were also included.
Linda Winger, MSc, FACHEGeorgetown University Medical CenterTables

Table 2 on page 7 provides a comparison of the different types of external beam radiation therapy (EBRT) modalities including SBRT. However, the technology assessment lumps together different types of technologies considered SBRT and fails to point out the differences especially for CyberKnife. Martin and Gaya (Martin A, Gaya A. ?Stereotactic Body Radiotherapy: A Review.? Clinical Oncology 2010, doi:10.1016/j.clon.2009.12.003) state that a number of modern linacs with on-board imaging capabilities meet the basic image guidance requirements for delivery of SBRT, e.g., Varian Trilogy and Elekta Synergy. More recently there has been the introduction of linacs fully adapted as integrated stereotactic delivery systems. These include the Novalis TX, BrainLAB, Elekta Axesse, TomoTherapy Hi-Art System, and CyberKnife. Sahgal 2008 (Sahgal A, et al. ?Stereotactic Body Radiosurgery for Spinal Metastases: A Critical Review. Int J Radiat Oncol Biol Phys 2008;71:652-665) provides details regarding the differences between the SBRT systems. The article indicates that the CyberKnife and Novalis systems are equipped with in-room stereoscopic kilovoltage (kV) X-ray imaging. However, the article goes on to state that the CyberKnife is unique in that it uses intrafractional X-ray imaging (typically 30-60 s), and automatic LINAC position adjustments to compensate for any detected changes in target positioning.

Since Table 2 on page 7 is demonstrably inaccurate in referring to the use of Stereotactic Immobilization for CyberKnife, and since CyberKnife has the ability to automatically track and compensate for target motion during treatment, we request that either additional columns should be added to the table, or that a new ?Advanced SBRT, such as CyberKnife? category should be created.

Thank you for your detailed information about the Cyberknife® system. Based on our search criteria, we did not find any comparative studies between Cyberknife® and other radiation therapy delivery systems that reported clinical outcomes.
Linda Winger, MSc, FACHEGeorgetown University Medical CenterFiguresIt is of interest within Figure 2 that proton therapy, which based upon the literature, is used only as boost therapy and has extremely limited data/publications, would be categorized as EBRT and not called out specifically just as SBRT was.Thank you for your comment about proton therapy data. We agree that proton therapy should ideally be compared to modern photon therapy, and have noted so in our report.

1Names are alphabetized by last name. Those who did not disclose name are labeled "Anonymous Reviewer 1," "Anonymous Reviewer 2," etc..
2 Affiliation is labeled "NA" for those who did not disclose affiliation.
3 If listed, page number, line number, or section refers to the draft report.
4 If listed, page number, line number, or section refers to the final report.

 

Page last reviewed August 2014
Internet Citation: Table 2: Public Reviewer Comments: Disposition of Comments. August 2014. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/research/findings/ta/localized-prostate-cancer/table2.html