For Protocol Amendment 10 to: RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis

Transcription

1 For Protocol Amendment 10 to: RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis NCI/Local Protocol #: RTOG-0631/RTOG 0631 NCI Protocol Version Date: September 26, 2016 Section Footer Title pages Administrative Changes The version date was updated This amendment was added to the Document History table. Index, Schema, 3.1.9, 10.0, Appendix I Sample Consent Form Appendix I was removed from the protocol because it is a stand-alone document, and the remaining appendices were renumbered. Note: The Sample Consent Form became a stand-alone document in Amendment 9 (version date 8/14/15; broadcast date 8/24/15). This change was inadvertently not noted in the Summary of Changes for that amendment. The stand-alone MS Word version of the consent was accurately amended in Amendment 9; the embedded Appendix in the PDF version of the protocol was not amended , The Functional Assessment of Cancer Therapy-General (FACT-G) website active hyperlink was replaced with the specific website address The Brief Pain Inventory (BPI) website was corrected , , The NCI Common Terminology Criteria for Adverse Events (CTCAE) version number was corrected from 4.0 to 3.0 for consistent use of the same CTCAE version throughout the study phases Section 5 was updated throughout to reflect the current process: The Access Requirements were expanded (5.0); A description of the Investigator Registration Requirements was added (5.1); Text specifying mandatory post-treatment imaging was added (5.3); The IRB approval text was added to reflect current guidelines (5.5); All subsections were renumbered accordingly ( ).

2 Section Administrative Changes In Paragraph 2, adverse event reporting was specified as routine. The phrase case report form was added to specify the documentation tool for adverse event reporting. The reference and hyperlink to CTCAE version 4 were deleted. The sentence referencing treatment center access to version 4 also was deleted. In Paragraph 3, text was added to specify that CTEP-AERS utilizes the NCI CTCAE version 4.0. CTEP Adverse Event Reporting System was deleted because it is redundant (this definition is already provided in the section header), and application accessed via either the CTEP web site was corrected to and the application can be accessed via the CTEP web site Paragraph 4: This is a new paragraph added to clarify that all treatment centers should have access to both versions 3 and 4 of the CTCAE because both are still in active use for this study, and also to clarify the location of these forms. In Paragraph 5, the out-of-date citation to the CTEP, NCI Guidelines for Adverse Event Reporting Requirements was deleted. In Paragraph 13, the NRG Oncology phone number was updated and CTEPP was corrected to CTEP in Bullet 1. The beginning of the 3 rd sentence of Bullet 2 was corrected to Supporting source documentation should include because elements of the CTEP-AERS report are required and not conditional. Also the fax number was deleted and 4 th sentence was added with the NRG Oncology contact number for instructions on submitting supporting documentation. 10.1; 10.2; 10.5; Appendix IV; Appendix V References to the NRG Oncology Biospecimen Bank were updated to be consistent with NCTN terminology, and the address was corrected. 10.4; Appendix IV; Appendix V The specimen collection summary and instructions were updated to reflect current Biobank policies and processes ; References to the RTOG and RTOG studies were corrected to include reference to NRG Oncology.

3 For Consent Amendment 10 to: RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis NCI/Local Protocol #: RTOG-0631/RTOG 0631 NCI Protocol Version Date: September 26, 2016 Section Header & Footer Change A header with version date was added per current NRG Oncology standard, and page numbers were added. Title Page The heading Appendix I was deleted because the consent has been removed as an appendix within the protocol.

4 For Protocol Amendment 9 to: RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis NCI/Local Protocol #: RTOG-0631/RTOG 0631 NCI Protocol Version Date: August 14, 2015 Section Change Footer The version date was updated Title pages This amendment was added to the Document History table The protocol was amended to clarify that: (1) the 3-month time point for the Numerical Rating Pain Scale (NRPS) is required and if not submitted, the sites must submit a protocol deviation to their IRB; and (2), the physician can ask the patient for his/her pain score and record it in the chart and on the F1. Related changes are as follows: 2 nd paragraph, 2 nd -to last sentence: (required) added after 3 ; 2n paragraph, last sentence: added Follow-up Form (F1) row: (NRPS-required at 3 months) added after 3 as explained above 12.2 Digiial data submission logistics were updated per current process. Appendix II An asterisk was added after Numerical Pain Scale and documentation of patient s pain medication along with corresponding statement *NRPS at 3 months is required for analysis of the primary endpoint as explained above. For Consent Amendment 9 to: RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis NCI/Local Protocol #: RTOG-0631/RTOG 0631 NCI Protocol Version Date: August 14, 2015 Section Header Change A header with version date was added per current NRG Oncology standard. During the study The 4 th sentence, You will rate your pain compared to the pain you experienced at the time you enter the study, was added for clarity and consistency with the protocol. Study Plan In part B, 3 rd to last and 2 nd to last boxes: start treatment was corrected to enter the study.

5 For Protocol Amendment 8 to: RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis NCI/Local Protocol #: RTOG-0631/RTOG 0631 NCI Protocol Version Date: April 14, 2015 Section Title pages Change On the 1 st title page, the address of the Senior Statistician was amended and her address was corrected. On the 2 nd title page, this amendment was added to the Document History table. Eligibility Checklist On page 2, question 18 was added to amend the checklist to current NRG Oncology standard text This section was amended to current NRG Oncology standard text. For Consent Amendment 8 to: RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis NCI/Local Protocol #: RTOG-0631/RTOG 0631 NCI Protocol Version Date: April 14, 2015 Section Global How many people will take part in the study? Change Sections referring to Part A were shaded in grey as is consistent with NRG Oncology standards, to indicate that this part of the trial has been completed. The number of participants for Part B was corrected from 380 to 352 to be consistent with the protocol. About Using Blood and Urine for Research In the 1 st paragraph, the reference to the NCI tissue information sheet was deleted because it is no longer available on the cancer.gov website. Five paragraphs were added to Risks to amend the sample consent to current NRG Oncology standard text.

6 For Protocol Update to: RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis NCI/Local Protocol #: RTOG 0631 NCI Protocol Version Date: April 21, 2014 Update Date: June 27, 2014 (Broadcast June 27, 2014) Section Change Cover page The document history table was updated to include the updated date. Schema page The sample size was corrected from 380 to 352 patients. Eligibility Checklist Question wording was adjusted to match questions asked at Oncology Patient Enrollment Network (OPEN) registration The OPEN registration system will now be used to register patients to this study. The registration text was updated accordingly In the last sentence, the non-compliance rate was corrected from 15% to 10% Appendix I/ Sample Consent No changes were made.

7 For Protocol Amendment #7 to: RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis NCI/Local Protocol #: RTOG 0631 NCI Protocol Version Date: April 21, 2014 (Broadcast May 13, 2014) Section Change Due to the transition to the National Clinical Trials Network (NCTN), the protocol was revised throughout the protocol to include our new organization name, NRG Oncology. References to RTOG were modified as appropriate. Global As required by CTEP, references to the Adverse Event Reporting System (AdEERS) have been changed to CTEP Adverse Event Reporting System (CTEP-AERS) throughout the protocol. Cover pages The document history table was updated to include Amendment 7. Contact information was updated for Drs. Ryu, Gerszten, Yin, and Pugh. Schema page The sample size was increased from 240 to 380 people to account for a death rate of 15% at 3 months, which is similar to that of RTOG 9714 (Chow 2005 JNCI) and a patient non-compliance rate of 15% As requested by NCI, CTEP Active version of the CTCAE was replaced with NCI Common Terminology Criteria for Adverse Events (CTCAE) version , 13.3 Due to the transition to the NCTN, the Radiologic Physics Center (RPC) was updated to its new name, IROC (Imaging and Radiation Oncology Core) Houston, and corresponding web site. Credentialing logistics were revised as appropriate contrast is not required but strongly recommended was added in parentheses for clarity Section numbering was corrected from Section was deleted because it is not necessary. Since there are no drugs in this study, Health Canada forms are not required. Remaining sections were appropriately renumbered. 6.4 The critical structures table was updated per current process.

8 Section Change The last sentence was deleted because it is no longer applicable. 6.7 In the 4 th paragraph, the process for RT quality assurance review was updated to current standard In the last sentence before the gender and minorities table, it was clarified that the projected accrual is for both phases. For Protocol Consent Amendment #7 to: RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis NCI/Local Protocol #: RTOG 0631 NCI Protocol Version Date: April 21, 2014 (Broadcast May 13, 2014) Section How many people will take part in the study? Possible Side Effects of Radiosurgery/ SBRT Possible Side Effects of Standard Radiation Will my medical information be kept private? Change The number of people was increased from 240 to 380 people as described above. The format and headings were changed to be consistent with CTEP s guidelines for listing risk profiles in informed consents. Radiation Therapy Oncology Group (RTOG) Headquarters was updated to NRG Oncology Statistics and Data Management Center in the 1 st sentence of the 1 st paragraph; The Radiation Therapy Group was revised to NRG Oncology in the 1 st bullet.

9 SUMMARY OF CHANGES Update: November 22, 2013 (Broadcast: November 22, 2013) RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis Study Chair: Samuel Ryu, MD; ; RTOG 0631 has been updated as follows: Section 3.0: Contact information for eligibility questions was added per current RTOG standard text. Section 5.0: RTOG is now using TRIAD to collect RT digital data. TRIAD provides sites participating in RTOG clinical trials with a secure method to transmit DICOM RT and other digital data. TRIAD anonymizes and validates the images and information objects as they are transferred via the internet. The first paragraph was added to update the protocol with access requirements for TRIAD. Sections 5.1, 5.2: These sections were updated to current RTOG RTQA standard text. Section 5.3: This section was added to update the protocol with instructions regarding submission of digital RT data using TRIAD (and subsequent sections were appropriately renumbered). Section 5.5: Web support address was updated. Section 6.2.3: The last paragraph was updated to RTOG RTQA standard text. Section 6.4: This section was updated to RTOG RTQA standard text. Table 1 was added and the subsequent table was renumbered appropriately. Section 6.4.2: This section was updated for clarity. Section 6.7: 2 nd paragraph was updated per RTOG RTQA standard text. Section 6.10: This section was updated per current CTEP standard text. Sections 10.2 and 10.5: These sections were updated per current Biospecimen Resource standard text. Section 12.2: This section was updated per current RTOG standard text. Section : This section was deleted. ITC will no longer be utilized for data submission for this trial. Digital data will be submitted to TRIAD. Appendix V and Appendix VI: This section was updated per current Biospecimen Resource standard text.

10 SUMMARY OF CHANGES Amendment 6, Version Date: May 6, 2013 (Broadcast May 16, 2013) RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis Study Chair: Samuel Ryu, MD; ; RTOG 0631 was amended as follows: The protocol was originally written for localized spine metastasis to a maximum of 3 sites, based on bone scan or PET scan of the spine. However, MRI of the involved spine (such as T spine MRI) is required to confirm the diagnosis and to use for treatment planning. In addition, since the protocol was initially written, there has been wider clinical use of entire-spine MRI scans to detect spine metastasis. These MRI scans can detect tiny metastatic lesions within the vertebral bodies that are not detectable on bone scan or PET scans, and they can unnecessarily render certain patients with multiple spine metastases ineligible: most of these lesions are not symptomatic and thus may not require local radiation therapy. The primary endpoint of this trial is pain control. Therefore, the protocol was amended to restrict metastases to the number of painful spine sites ( 5 NRPS score) as an eligibility criterion, rather than the radiographically strict 3 spine metastasis maximum. This means that there can be multiple tiny spine metastases, as they are more often clinically encountered with MRI, provided that the number of painful sites is limited to 3. Related changes were made to the following sections: Schema: In the Number of Spine Metastases stratification factor with a 5 NRPS score was added after 1 and with 5 NRPS scores was added after 2-3. Eligibility Checklist question 1: sites with a 5 NRPS score was added. Eligibility Checklist question 24: with a 5 NRPS score was added after 1 and with 5 NRPS scores was added after 2-3. Section 3.1.1: Column (4) was added to the diagram. Section : The subsection was added. Section and corresponding eligibility checklist #15: Patients with any spine metastasis that is not planned to be treated per protocol was deleted. Subsequent sections/questions were renumbered. Other Changes Cover Pages: The document history table was updated to include Amendment 6. The participating sites list was added per current RTOG standard. Section : or who cannot be premedicated for the use of contrast dye was added to clarify that patients can be premedicated. Section 5.3.1: Regulatory Pre-Registration requirements were modified to current RTOG standard. Section 5.4.1: Contact information in event of RTOG web registration inaccessibility was updated. Section nd paragraph: The reference was updated from January 2005 to July 26, 2011.

11 4 th paragraph: including a male patient s impregnation of his partner was added per current RTOG standard. AdEERS reporting tables and related instructions: The text was updated to current standard. Section 10.4: In the DNA column, whole blood was added before DNA for clarity, and instructions to note any alternate collection time point was added. Section 10.5: The mailing address for the RTOG Biospecimen Resource was updated.

12 SUMMARY OF CHANGES Amendment 5, Version Date: May 1, 2012 (Broadcast May 3, 2012) RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis Study Chair: Samuel Ryu, MD; ; RTOG 0631 was amended as follows: Global: Formatting and punctuation errors were corrected as needed. Title Page: The document history table was updated to include Amendment 5. Section 10.5 and Appendices V and VII (RTOG Blood and Urine Collection Kit Instructions): The mailing address for the RTOG Biospecimen Resource was updated. Section 11.4: The last sentence was deleted because it was included in error. Appendix I (Informed Consent) What will happen if I take part in this research study? o If you are in Group 1, 3 rd to last sentence: The sentence was deleted because it was included in error o If you are in Group 2, 1 st sentence: after a planning session was added for increased accuracy Will my medical information be kept private?: The last paragraph was added to comply with FDA requirement for new element of consent as found in 21 CFR 50.25(c). Where can I get more information?: The NCI TTY number was deleted because it is no longer in service.

13 SUMMARY OF CHANGES Amendment 4, Version Date: August 30, 2011 (Broadcast September 23, 2011) RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis Study Chair: Samuel Ryu, MD; ; RTOG 0631 has been amended as follows: A. The single fraction d ose for Arm 1 was amended from 16 Gy t o 16 o r 18 Gy, as additional experience of radiosurgery with higher doses for spine metastasis suggest that a higher (than 16 Gy) ra diosurgery dose was required to achi eve similar pain relief, particularly in radi oresistant tumors. The follo wing sections were amended for thi s change: Schema page, Eligibility Checklist; and Sections 1.3, 1.4, 1.5, 2.1.2, , (2 nd paragraph and item 1), and B. Two stratification variables were added to prevent bias of results, Type of Tu mor and Intended Radiosurgery/SBRT Single Fraction Dose. The following sections have been amended for this change: Schema page (addition to phase III c omponent table and asterisk (*) below; Eligibility Checklist, page 3 (question 25 was added); Section 1.5 (amended); Section was added; and Section (amended). Other Changes Schema page: The Schema for the phase II component was shaded and under Required Sample Size, the word, completed was added to indicate that accrual to this component of the study has finished. Eligibility Checklist, page 3: Questions 21 and 22 were corrected to 23 and 24., Question 24 was reformatted for database purposes. In addition, Question 26 was added. Section 1.3: In the 2 nd paragraph, in the 2 nd to last sentence, the phrase, the phase III component of was added prior to this study for clarity. Section 3.1.1: The last sentence was added to clarify that patients can have other systemic metastasis and that radioresistant tumors (including soft tissue sarcomas, melanomas, and renal cell carcinomas) are eligible. Question 13 on page 1 of the Eligibility Checklist was amended to be consistent with this change. Section 3.1.8: The sentence, Documentation of the patient s initial pain score is required, was added for clarity. This change also was made in Section 4.1.1, 2 nd paragraph, and in Section Section 3.2.1: was amended to be consistent with changes in Section and with the addition of stratification by type of tumor. Question 13 on page 1 of the Eligibility Checklist was amended to be consistent. Section 4.1.1, 1 st paragraph: The last sentence, stating that the patient can be on pain medication, was added for clarity. Section was amended for clarity. Section : The last paragraph and table were deleted, as these were necessary for the feasibility component (phase II) of the study but are not for the phase III component. For the phase III component, IGRT will no longer be reviewed and scored but will be submitted. Section 6.0: In the Note, Section 6.1 was amended to Sections for accuracy, and a sentence was added referring investigators to Section for IGRT requirements for Arm 1.

14 Section : In the 1 st paragraph, the 2 nd sentence was added for clarity, and the phrase, target volume, was added to the 3 rd sentence for clarity. In addition, the 2 nd paragraph was replaced with a reference to the cord dose/volume constraints in Section The following changes were made in Section : In the 3 rd paragraph, the word, partial was added prior to spinal cord in the 5 th sentence for clarity. The 4 th paragraph was amended to clarify spinal cord constraints and dosimetric requirements. In Figure 3, Spinal cord was amended to Partial spinal cord for clarity. In the 1 st sentence of the 5 th paragraph, the word, constraint, was corrected to constraints. The following changes were made in Section 6.3.2: In the 3 rd paragraph, item 2, Target Dose Heterogeneity, the word, acceptable, was updated to per protocol. In the 3 rd paragraph, item 4, Spinal Cord Dose, was amended to clarify the spinal cord dose. Section 6.4.1: A Note was added to the 1 st paragraph to clarify that the dose to the spinal cord in the study has been modified from the Timmerman 2008 publication. In Table 1, the Volume and Volume Max for the spinal cord were reformatted and amended for clarity. Also, in the Volume column, for all tissue areas from Cauda Equina through Rectum, the volume was simplified from <0.035cc to <0.03cc. Section was amended to clarify the spinal cord dose. In addition, a citation was added to the parenthetical phrase. Section : In the 1 st sentence, the phrase, requires no less, was corrected to requires no more. Section 6.5.1: The last sentence was added, instructing investigators that IGRT data must be submitted for Arm 1 patients, and Section was referenced. Section 6.6: The phrase, for Arm 1 Spine Radiosurgery, was added to the heading for clarity. Section : Under Per Protocol plan, the last bulleted item was deleted, as a 2 nd constraint for doses outside the target volume is unnecessary. Section 6.6.2: IGRT was added to the heading of the section for clarity. In addition, the 1 st sentence was added to provide instructions to sites. Section 6.7: The last sentence was added to the 4 th paragraph, referring investigators to the AAPM TG 142 report for detailed QA information. The following changes were made in Section 6.8.1: Section : The phrase, for 2D and 3D Treatment, was added to the heading for clarity. The 2 nd sentence was amended for clarity. The last sentence was added to provide instructions to investigators. Section : In the last paragraph, the word, radiosurgery was replaced by external beam treatment for clarity. The following changes were made in Section 6.8.2: Section : The phrase, or 3D conformal therapy at the treating physician s discretion, was added at the end of the 2 nd sentence for clarity. Section was amended for clarity. The following changes were made in Section 6.8.3:

15 The 1 st five paragraphs were reformatted as Section , under the heading, 2D Treatment. In the 1 st paragraph of Section , the last sentence was added for clarity and to be consistent with Section In the 2 nd paragraph of Section , the last sentence was moved to be the last sentence of the 5 th paragraph for clarity. A new section, , 3D Treatment, was added. Section 6.8.4: The 1 st sentence was added to refer investigators to Section 6.4.1, Table 1. The 2 nd sentence was amended for 2D treatment, and the 2 nd paragraph was added to provide details of 3D treatment. Section 6.8.5: Sections were added to provide instructions to sites for documentation requirements for 2D and 3D treatment. Section 6.8.6: The phrase, for 3D Treatment, was added to the heading and the text was amended to provide criteria for 3D treatment. Section was added to provide compliance criteria for 2D treatment. Section was amended as required by CTEP. Section 10.1: In the 2 nd paragraph, lymphocytes was replaced with whole blood to update the protocol to current RTOG Biospecimen Resource standard text. In addition, the last sentence of the 2 nd paragraph was amended to clarify that serum, plasma, whole blood and urine will be collected at baseline, and that serum, plasma, and urine will be collected at 3 months from randomization. In addition in the 4 th paragraph, buffy coat was replaced with whole blood to update the text to current Biospecimen Resource text. Section 10.2: The heading and text was amended to current RTOG Biospecimen Resource standard text. Section 10.3: The text from the previous Section 10.5 was moved here to be more current with RTOG Biospecimen Resource standard text for Section 10.0, and subsequent sections were appropriately renumbered. Section 10.4: The heading and table were amended to current RTOG Biospecimen Resource standard text. Section 10.5: The phrase, U.S. Postal Service, was added prior to Mailing Address to update the protocol to current RTOG Biospecimen Resource standard text. Section 10.6 was amended to current RTOG standard text. The following changes were made in Section 12.2: The schedule for Digital Data Submission was amended for clarity to read, Within 1 week post-radiosurgery & 3D-CRT external beam, and a reference to Section 6.0 was added parenthetically. Next to Final Dosimetry Information, the phrase, All Cases was added, and the schedule was amended for clarity to read, Within 1 week of RT. Next to IGRT Submission, the phrase, Arm 1 Only, was added parenthetically for clarity. A reference to Section was added after the IG form. A Note was added to provide instructions to sites regarding 2D cases. The following changes were made in Appendix I: Under Why is this study being done?, a sentence was added after Part A to inform patients that enrollment to this part of the study has been completed.

16 Under About Using Blood and Urine for Research, the 1 st paragraph was amended and a sentence was added to the 3 rd paragraph to update the protocol to standard NCI consent text. Appendix II: The table for the phase II component was shaded to indicate that accrual to this component of the study has finished and to be consistent with changes made to the Schema page. Appendices V and VI were amended to current RTOG Biospecimen Resource standard text.

17 SUMMARY OF CHANGES Amendment #3: March 18, 2011 (Broadcast: 5/19/11) RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis Study Chair: Samuel Ryu, MD; ; RTOG 0631 has been amended as follows: As mandated by CTEP, beginning July 1, 2011, this study will utilize CTCAE version 4.0 for reporting of all adverse events. Related changes were made to Section 6.10, 9 th paragraph. Global: All web links to sub-pages of RTOG web site were updated. Cover Page Stephanie Shook has replaced Meihua Wang as the Senior Statistician. A document version history was added to the Cover Page per current RTOG standard. Section 5.3.1: The link to the Certification Form was updated, and the option to the CTSU Regulatory Office was added. Section was updated to current RTOG standard text. Section : the link to the LOI form was updated. Section 6.10, 5 th to last paragraph: The paragraph beginning AdEERS provides a radiation therapy (RT)-only pathway was deleted because it already is included earlier in the same section.

18 SUMMARY OF CHANGES Amendment #2: March 11, 2010 (Broadcast: 3/23/10) RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis Study Chair: Samuel Ryu, MD; ; RTOG 0631 has been amended as follows: Eligibility Checklist, question 16, page 1 of 3: The question was rewritten for consistency with Section Section 3.2.2: The criterion was revised to more accurately describe the original intent The criterion was also added to the Eligibility Checklist as question 15, and all subsequent questions were appropriately renumbered. Section 6.0, 4 th paragraph: Protocol treatment must begin with 4 weeks after MRI of the involved spine was changed to Patient registration must be done within 4 weeks after MRI of the involved spine to due the protocol s intended logistics. Section 6.3.2, Section 1/Prescription Isodose Surface Coverage, last sentence and Section 6.6.1, 2 nd sentence: Minor Violation was corrected to Variation Acceptable and Major Deviation was corrected to Deviation Unacceptable per current RTOG standard. Section 6.3.2, Section 3/High Dose Spillage: The subsection heading for a) location was deleted and the entire section was revised and expanded to include more complete compliance criteria. Section 6.3.2, Section 4/Spinal Cord Dose: The subsection heading and number were revised and clarified from b) Volume due to protocol intent and due to the deletion of the a) subsection as described above. Section 6.4.2: The first sentence was added for clarity and accuracy. Section : The entire section was added for clarity and accuracy. Sections and , 1 st sentence: Month 9 was deleted from the assessment list because it was inadvertently included.

19 SUMMARY OF CHANGES Amendment #1: November 6, 2009 (Broadcast: November 19, 2009) RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis Study Chair: Samuel Ryu, MD; ; RTOG 0631 has been amended as follows: As mandated by CTEP, the CTCAE version referred to in the protocol was revised from v. 3.0 to the CTEP Active Version of CTCAE. Changes were made to the following sections: Section Section 6.10, 9 th paragraph and 4 th -to-last paragraph Section Section Other changes Eligibility Checklist, question 16, page 1 of 3: 50% was corrected to > 50%, for consistency with Section Eligibility Checklist, question 14, page 2 of 3: Patient s insurance status was changed to Method of payment per current RTOG standard. Section 5.4, 2 nd -to-last paragraph: The address was updated for web support. Sections /i, /f, /h, and /d: Text concerning storage information was replaced with a reference to see Section Section 10.5: A section on storage conditions was added per current RTOG standard. Subsequent sections were appropriately renumbered. Section 12.2: The web address was updated for DDSI submission. The address for ITC was updated. Appendix I/Sample Consent Before you begin the study, 1 st bullet: The neurologic examination does not need to be performed by a neurologist. The text was therefore revised from including an examination by a neurologist to test the brain and nervous system to including a neurologic examination (an examination to test the brain and nervous system) What will happen if I take part in this research study?, Part A/2 nd paragraph/1 st sentence and Part B/2 nd paragraph/4 th sentence: For timing clarity, the text was revised from You will then receive one high dose radiation treatment to your spine to Within a few days following your treatment planning session, you will receive one high dose radiation treatment to your spine Appendices V/Blood Collection and VI/Urine Collection: The text was replaced with current RTOG standard.

20 SUMMARY OF CHANGES Update: December 1, 2009 (Broadcast: December 1, 2009) RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis Study Chair: Samuel Ryu, MD; ; RTOG 0631 has been updated as follows: Sections 10.7 and 10.8: The Reimbursement and Confidentiality/Storage sections were renumbered from 10.6.and 10.7, respectively, due to a numbering error in the 11/6/09 amended version.

21 SUMMARY OF CHANGES Update: August 11, 2009 (Broadcast: 8/11/09) RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis Study Chair: Samuel Ryu, MD; ; RTOG 0631 has been updated as follows: Section 6.7, 1st sentence: 1st case from each institution was corrected to first 2 cases from each institution

22 SUMMARY OF CHANGES Update: August 7, 2009 (Broadcast: 8/7/09) RTOG 0631, Phase II/III Study of Image-Guided Radiosurgery/SBRT for Localized Spine Metastasis Study Chair: Samuel Ryu, MD; ; RTOG 0631 has been updated as follows: Eligibility Checklist, page 1: A subquestion was added to Question 1, asking sites to specify the screening imaging study. No eligibility criteria were changed.