IPAC date: 8 September of 10

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National Institute for Health and Care Excellence

IP1316 – Biodegradable spacer insertion to reduce rectal toxicity during radiotherapy for prostate

cancer

Consultation Comments table

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2 of 10 Com.

no. Consultee name and organisation

Sec. no. _Comments _Response

Please respond to all comments

1 Consultee 1 Professional organization British Uro-oncology Group (BUG)

General There is enthusiasm amongst clinical oncologists to have access to biodegradable spacers for insertion into the perirectal space in order to reduce rectal toxicity for men treated with radiotherapy for prostate cancer. Radical radiotherapy is an established and potentially curative therapy option for men with prostate cancer. The rectal toxicity experienced by men treated with radiotherapy can be associated with considerable cost in terms of toxicity including potential rectal bleeding, bowel ulceration, bleeding, diarrhoea and incontinence. In addition these side effects represent an economic burden to healthcare with the necessity for clinical assessment and investigation by bowel clinicians and the need for surgical procedures. We therefore welcome this development of prerectal spacer insertion prior to radiotherapy which could reduce these debilitating side effects and improve the quality of life for men following radiotherapy treatment.

Thank you for your comments. 2 Consultee 1 Professional organization British Uro-oncology Group (BUG)

1.1 We agree with the NICE recommendation that there are no concerns regarding the safety and tolerability of this procedure and this has been very well demonstrated in both randomised studies and case series.

Thank you for your comments.

Section 1.1 states that ‘the evidence on insertion of a biodegradable spacer to reduce rectal toxicity during radiotherapy for prostate cancer raises no major

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1.1& 4 We would however challenge the statement regarding the efficacy of this procedure as there is good evidence that the insertion of a spacer significantly reduces the measured radiotherapy dose to the rectum from the analysis of Dose Volume Histograms. In the pivotal multicentre prospective randomized controlled trial conducted by Mariados, 97.3% of Spacer patients experienced a ≥ 25% in rV70. This is a strong and recognised surrogate outcome factor for a reduction in late radiotherapy toxicity. The reduction of radiotherapy dose to critical organs at risk is an established outcome that is used to change radiotherapy practice and this has been achieved in both this prospective study and numerous case reports.

In that document is it stated that existing clinical long-term rectal toxicity and patient outcome data is inadequate requiring the “special arrangements” classification. This recommendation was understandably based on literature available at that time, with follow up limited to 15 months. However, three additional biodegradable spacer studies have recently been published, with follow up time out to 28 months. We believe that these new data provide adequate long-term data demonstrating reductions in rectal toxicity and improvements in patient outcomes, justifying a “normal controls” classification.

Published evidence on efficacy from the randomised controlled trial by Mariados (2015) and Yeh (2016) has been included in section 4 of the guidance and table 2 in the overview.

Whalley et al (2016) has been picked up in our update search and has been added to the table 2 in the overview. Pinakwa et al (PO-0738- presented at ESTRO meeting) is a conference abstract and only safety data is considered.

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4 of 10 3 Consultee 1 Professional organization British Uro-oncology Group (BUG)

1.1 & 4 Briefly, those studies are summarized here:

At the ESTRO meeting in 2016 Pinkawa (PO-0738) presented longer term follow up data for men treated with prostate radiotherapy. 108 men had a spacer insertion prior to treatment with 94 men in a control group treated with radiotherapy alone. Despite the Spacer patients receiving higher prescription doses, at 17 months:

Spacer mean bowel bother score did not change from baseline to measurement greater than a year after therapy for spacer patients but was reduced to -7 in controls (p<0.01). Control patients had more "bloody stools", "painful bowel movements" and "frequency of bowel movements" (p< 0.05). Of patients with no bowel issues at baseline, 0% (Spacer) vs. 12% (Control) reported moderate/big bowel problems at 17mo (p<0.01). Endoscopic examinations were performed in 4% (Spacer) and 17% (Control) of patients (p<0.01)

A recently published article by Yeh et al reports on 16 month toxicity scores in 326 men following the insertion of a prerectal spacer prior to prostate radiotherapy. The rates of late Grade 1, 2, and 3 rectal toxicity were 12.7%, 1.4%, and 0.7%, respectively. There were no late Grade 4 toxicities A third publication from Whalley et al reports on 140 men (30 Spacer, 110 Control) with a median follow up of 28 months. The rates of acute grade 1 and 2 GI toxicity was 43% versus 51% and 0% versus 4.5% in the Spacer and Control groups, respectively (p>0.05). The late grade 1 toxicity was significantly less frequent in the Spacer group (16.6% versus 41.8%, p=0.04). 4 Consultee 1 Professional organization British Uro-oncology Group (BUG)

1.1 & 4 These results and further late follow up from other studies demonstrate the evolving significant long term benefits that have been predicted by the Dose Volume histogram calculations. These new data provided further compelling evidence that biodegradable spacer insertion be classified as “normal assignment”.

See response to comment 3 and 5.

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4 In addition to these three studies, a 37 month follow up study on the prospective randomized hydrogel spacer clinical trial (initial paper: Mariados, et al) has recently been completed and it is anticipated that these results will be published in October 2016. We would urge NICE to consider the new data and also to wait for the long term toxicity results from the prospective randomised study before making a final decision on this subject.

This study is not yet

published. Efficacy data that have not been published or accepted for publication by peer reviewed journals are not normally selected for presentation to the committee. Therefore,

currently the long term follow-up results from this study will not be included in the

guidance or table 2 in the overview. IP team has followed up with the authors about the upcoming

publication but did not receive any definite publication dates. IPAC may review the

guidance upon publication of new evidence in peer

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6 of 10 6 Consultee 1 Professional organization British Uro-oncology Group (BUG)

1 In conclusion, as acknowledged in the consultation document, the procedure is safe, and there are many studies demonstrating the significant rectal dose reduction that results from the use of these devices. The addition of these three new publications, and the upcoming publication of the 37 month follow up data, all provide additional data on long-term reductions in rectal toxicity and improvements in quality of life.

Thank you for your

comments. See response to comment 3.

IPAC considered the additional new study

published (Whalley 2016) and included it in table 2 of the overview.

IP team has followed up with the authors about the

upcoming publicationbut did not receive any definite publication dates. 7 Consultee 2 Professional organization Royal College of Physicians

1 The NCRI-RCP-ACP-RCR are grateful for the opportunity to respond to the above consultation. Our experts support the recommendations within the consultation document, which are entirely appropriate.

Consultee agrees with the recommendations in section 1 of the guidance.

8 Consultee 3 Manufacturer

1.1 I read with interest your recent consultation document regarding the use of biodegradable spacers to reduce rectal complications in men undergoing prostate radiotherapy. First, my compliments on your thorough review and fair treatment of the literature. Of note, the assignment to special arrangements was based on inadequate long term data demonstrating rectal toxicity reductions and improved patient outcomes (section 1.1).

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4 Since completing your literature review at least three separate studies have been published significantly increasing the long term data available. These studies show spacer safety and efficacy out through 28 months, addressing the data deficiency stated in the consultation document. As such these studies should be included in the document.

Yeh et al1_{followed 326 PEG hydrogel spacer patients out}

through 16 months with low rectal toxicity rates. Pinkawa et al2_{followed PEG hydrogel and control patients (202 total)}

through 17 months and found significant bowel QOL improvements. Whalley et al3_{followed 140 PEG hydrogel}

and control patients through 28 months and found significant reductions in grade 1 rectal toxicity in the spacer group.

1. (Yeh J, Lehrich B, Tran C, et al. Polyethylene glycol hydrogel rectal spacer implantation in patients with prostate cancer undergoing combination high-dose-rate brachytherapy and external beam radiotherapy. Brachytherapy. 2016 May-Jun;15(3):283-7.

2. M. Pinkawa, V. Schmitt, V. Djuktc J. et al. Hydrogel injection prevents long-term rectal toxicity after radiotherapy for prostate cancer. PO-0738 ESTRO 35, 2016.

3. D. Whalley, G. Hruby, F. Alfieri, et al. SpaceOAR Hydrogel in Dose-escalated Prostate Cancer Radiotherapy: Rectal Dosimetry and Late Toxicity. Clin Oncol (R Coll Radiol). 2016 Jun 10)

Reference 1 (Yeh 2016) has already been included in section 4 of the guidance and table 2 in the overview.

Reference 2 (Pinkawa 2016) presented at ESTO meeting is a conference abstract and only safety data is

considered.

Reference 3 (Whalley 2016) has been picked up in our update search and has been added to table 2 in the overview.

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8 of 10 10 Consultee 3

Manufacturer

4 Finally, a recent evaluation of the SpaceOAR US Randomized Controlled study has been completed, with a median follow up of 37 months. While not yet published, the results support these three recent publications, demonstrating a durable benefit to patients with reduced rectal toxicity and improved quality of life. Publication of this data is expected Q4 2016.

This study is not yet

published. Efficacy data that have not been published or accepted for publication by peer reviewed journals are not normally selected for presentation to the committee. Therefore,

currently the long term follow-up results from this study will not be included in the

guidance and table 2 in the overview.

IP team has followed up with the authors about the

upcoming publication but did not receive any definite publication dates. IPAC may review the

guidance upon publication of new evidence in peer

reviewed journals. 11 Consultee 3

Manufacturer

1.1 Because these recent studies address the lack of long term data mentioned in the draft document please consider assigning the procedure to normal arrangements going forward.

see response to comment 3 and 5.

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1.1 & 1.2 I am writing in response to the draft recommendations from the NICE Interventional Procedure consultation document titled “Biodegradable spacer insertion to reduce rectal toxicity during radiotherapy for prostate cancer”, dated June 2016.

Page 2 of the consultation document (section 1.1) states that “The evidence on insertion of a biodegradable spacer to reduce rectal toxicity during radiotherapy for prostate cancer raises no major safety concerns.” Additionally, page 3 (section 1.2) states that clinicians wishing to insert a biodegradable spacer to reduce rectal toxicity during radiotherapy for prostate cancer should . . . ensure that patients understand the uncertainty about the procedure’s safety and efficacy.” This clear discrepancy should be resolved. If NICE has no major safety concerns about the insertion of a biodegradable spacer, then why should clinicians state there is uncertainty about the procedure’s safety?

IPAC amended bullet point 2 in section 1.2 as follows Ensure that patients

understand the uncertainty about the procedure’s efficacy, and provide them with clear written information. In addition, the use of NICE’s

information for the public is

recommended.

General This letter is to provide additional information regarding the safety of SpaceOAR System. The polyethylene glycol (PEG) water based chemistry of the SpaceOAR System hydrogel is safe, non-toxic and non-immunogenic, and is widely used in many cosmetic, pharmaceutical and medical device products. Other approved PEG based products include DuraSeal® Dural Sealant and DuraSeal® Xact Sealant, ReSure® Ocular Sealant and the MYNXGRIP® Vascular Closure Device. Combined these products have been implanted in over two million of patients.

To date since receiving EU CE Mark in March 2010, Australian TGA approval in January 2011, US FDA clearance in April 2015 and Canadian licensure in February 2016, over 7,000 SpaceOAR® System units have been distributed worldwide, including approximately 3,000 units in the United States.

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10 of 10 14 Consultee 4

Manufacturer

5 Since initial commercial release the SpaceOAR System overall worldwide adverse event rate through June 2016 is 0.514%, comprised of 0.5% AE’s and 0.014% SAE’s. This commercial safety experience is consistent with the US SpaceOAR System pivotal randomized clinical trial results, during which no device related adverse events were reported through 15 months post device implantation.

1.2 In conclusion, with the established PEG hydrogel safety record, no device related adverse events in the prospective randomized clinical trial, and the very low commercial serious adverse event rate, the excellent safety profile of SpaceOAR System has been demonstrated. Therefore, we respectfully request removal of the statement that clinicians should inform patients about the “uncertainty about the procedure’s safety”.

IPAC amended bullet point 2 in section 1.2 as follows Ensure that patients

understand the uncertainty about the procedure’s efficacy, and provide them with clear written information. In addition, the use of NICE’s

information for the public is

recommended.

"Comments received in the course of consultations carried out by NICE are published in the interests of openness and transparency, and to promote understanding of how recommendations are developed. The comments are published as a record of the submissions that NICE has received, and are not endorsed by NICE, its officers or advisory committees."