Clinical trial NCT02017704
Conditions: Rectal Cancer
Keywords: Endorectal Brachytherapy Radiation Therapy Intensity Modulated Radiation Therapy and Capecitabine
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2014-06-12; Completion date: 2023-01-31
Enrollment: 9 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research is being done to compare the effectiveness of high dose endorectal brachytherapy (END-HDR) and the standard treatment option of chemoradiation with Capecitabine in the treatment of cancer of the lowest part of the bowel (rectum).

Detailed description:
Locally advanced rectal carcinoma continues to be a major oncologic problem in the United States with approximately 40,000 new cases diagnosed in 2011. For stage II/III rectal carcinoma, adjuvant chemoradiation and total mesorectal excision (TME) represent the major treatment advances that have increased cure rates over the past 30 years.

In the setting of TME, a landmark phase III German trial of stage II/III rectal cancer patients established neoadjuvant 5FU-based chemoradiation (NCRT) as standard of care over the same regimen given post-operatively. The preoperative arm showed superior local control (6% vs. 13% p=0.006), a complete pathologic response of 8%, a higher rate of sphincter preservation and less grade 3 toxicity compared to post-operative treatment. However, disease-free and overall survival (76% versus 74%, respectively) were no different because of the high rate of distant metastasis occurring in over 1/3 of patients (5yr DM 36 vs 38%,p=0.84). Importantly, those attaining a pathologic complete response had a decreased rate of distant metastasis and improved disease-free survival. Drawbacks to the regimen include acute grade 3 or 4 toxicity in 27% of patients, low compliance rates with postoperative chemotherapy (27 - 50%), and an overall decline in anorectal function shown by long-term studies.

Given the excellent locoregional control reported in TME surgical series, several trials have investigated whether certain patients may be spared preoperative radiotherapy. Two large randomized trials by Dutch and British investigators showed that a short preoperative course of hypofractionated EBRT (25 Gy in 5 fractions) followed by TME surgery decreased locoregional recurrence by 2/3 as compared to patients treated with TME surgery alone. In the Dutch trial, patients with mid and distal rectal cancers were most likely to benefit from radiotherapy. In these patients, preoperative radiation was shown to decrease locoregional recurrence by 5-fold (10% to 2%); however, the hypofractionated preoperative EBRT regimen was associated with a significant increase in acute and chronic morbidity. Indeed, the Dutch study revealed that irradiated patients, when compared to surgery alone, had more perineal wound healing problems after abdominoperineal resection (29% vs. 19%), worsening deterioration of anal sphincter dysfunction, and more severe long-term effects related to sexual functioning both in males (p=0.004) and females (p\<0.002). Additionally, colleagues have reported a consistent negative impact on bowel function in those patients undergoing sphincter preservation. In reviewing the long-term data of the Swedish short course preoperative EBRT rectal cancer trial, Birgisson also reported a higher incidence of secondary tumors (9.5%) in patients treated with preoperative radiation when compared to patients having surgery alone (4.3%).

Modern approaches to address the risk of distant metastasis and poor compliance with adjuvant systemic chemotherapy (following NCRT) have incorporated newer effective chemotherapy agents earlier in the treatment protocol. For example, oxaliplatin has been one of the most widely studied agents as a result of its proven efficacy when combined with 5-fluorouracil and leucovorin (FOLFOX) both in the metastatic and adjuvant settings for colon cancer. Initial phase II studies with the addition of oxaliplatin to standard 5-FU based NCRT appeared to show improved pathologic complete response rates compared to standard NCRT. However, two phase III trials clearly show that the addition of oxaliplatin during 5FU-based NCRT does not significantly improve pathologic complete response, locoregional control, distant metastasis or survival but does increase acute grade 3-4 toxicity by two to three-fold.

One approach to limit toxicity from external beam radiotherapy is the use of intensity modulated radiation therapy (IMRT). IMRT can limit radiation dose to normal rectum (above and below the tumor) and surrounding organs at risk (OARs) such as bladder and sexual organs. IMRT utilizes multiple beams of radiation to treat the rectal tumor plus a margin and limits dose to OARs. While IMRT decreases radiation dose to normal structures, it requires an additional 2-3 cm margin for microscopic extension (clinical treatment volume=CTV), set-up error, and rectal motion (planning treatment volume=PTV). Furthermore, IMRT still requires 5-6 weeks of radiation with concurrent chemotherapy, is substantially more expensive than conformal radiation, and is especially prohibitive in countries where access to technology necessary for IMRT is limited. Based on the preliminary results of RTOG 0822 and others, it still remains to be determined whether IMRT confers a statistically significant improvement in pCR, toxicity rates and QOL relative to standard NCRT.

A novel approach to limit radiation toxicity is the use of high dose rate endorectal brachytherapy (Endo-HDR). Endo-HDR involves the placement of a silicon multicatheter applicator within the rectum to deliver large doses to the rectal tumor and mesorectum with rapid dose fall off to the surrounding organs. An Iridium 192 high dose rate brachytherapy source attached to a wire is inserted into each catheter to deliver a high dose of radiation therapy the tumor. High dose rate brachytherapy has been well established in various malignancies (prostate, uterine, sarcoma, head and neck) to escalate radiation dose to the tumor over a short period of time while sparing normal tissue. Compared with NCRT and IMRT, Endo-HDR delivers treatment internally to the tumor without having to pass through surrounding normal tissue and organs. It requires smaller margins (CTV/PTV=\~1 cm) on the tumor since the applicator is positioned under fiducial guidance over the tumor without need for a margin for organ motion allowing greater sparing of OARs. Furthermore, the area of the rectum exposed to high dose radiotherapy is surgically removed at the time of resection which further minimizes chronic toxicity. Important structures that may be spared include bone marrow, small bowel, bladder, the autonomic nerves, sexual organs, anal sphincter and skin. Considering that 1/3 of patients will develop metastases, limiting bone marrow toxicity may contribute to better compliance with systemic treatment and allow for a better treatment strategy to target systemic recurrence. Another distinct advantage of Endo-HDR is the shortened treatment time (1 versus 6 weeks). Endo-HDR therefore provides a major logistic advantage for patients who may benefit from neoadjuvant therapy but who are geographically distant from radiation centers, elderly, or medically infirmed.

Arms: arm 1: Patients will receive IMRT along with capecitabine. External radiotherapy will be based on contouring guidelines from the RTOG atlas and Radiation Therapy Oncology Group (RTOG 0822) with some modifications

Followed by:

* Oxaliplatin: 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
* 5-Fluorouracil (5-FU) bolus 400mg/m² following the oxaliplatin/FA infusions
* 5-FU continuous infusion 2400 mg/m², 46-h infusion following the 5-FU bolus

Cycle length: 14 days (2 weeks)

Duration of treatment: 12 cycles

Then: Surgical Resection arm 2: Patients will be treated with a daily dose of 6.5 Gy over four consecutive days for a total of 26 Gy

Followed by:

* Oxaliplatin: 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
* 5-Fluorouracil (5-FU) bolus 400mg/m² following the oxaliplatin/FA infusions
* 5-FU continuous infusion 2400 mg/m², 46-h infusion following the 5-FU bolus

Cycle length: 14 days (2 weeks)

Duration of treatment: 12 cycles

Then: Surgical Resection
Interventions: intervention 1: Endo-HDR (if randomized to this arm) intervention 2: capecitabine and IMRT (if randomized to this arm) intervention 3: IMRT (intensity modulated radiation therapy) intervention 4: FOLFOX6 intervention 5: Surgery
Intervention descriptions: intervention 1: Patients will be treated with a daily dose of 6.5 Gy over four consecutive days for a total of 26 Gy intervention 2: Capecitabine shall be delivered at 825mg/m2 BID during IMRT radiotherapy intervention 3: Patients will receive IMRT along with capecitabine. External radiotherapy will be based on contouring guidelines from the RTOG atlas and Radiation Therapy Oncology Group (RTOG 0822) with some modifications intervention 4: * Oxaliplatin - 85 mg/m² in 500ml glucose 5% solution, 2-h infusion
* Leucovorin - bolus 400mg/m² following the oxaliplatin/FA infusions
* 5 Fluorouracil (5FU) - 2400 mg/m², 46-h infusion following the 5-FU bolus An outpatient, 46 hour continuous IV infusion provided by a home IV infusion company. The 5FU is delivered by a small pump worn in a fanny pack around the waist. The home IV infusion company will arrange your disconnect at the end of the infusion. intervention 5: After the patient has been identified as a candidate for the trial, the surgeon will assess the patient and will determine:

Exact height and location of tumor with regards to the anal margin as measured by a rigid or flexible proctoscope and/or digital exam.

Mobility of tumor as assessed if possible by rectal exam Type of surgical procedure: Abdominoperineal resection vs. sphincter saving procedures, which will include colo-anal with mucosectomy vs. stapled anastomosis.

Protocol documents:
Prot_SAP_000.pdf: 
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Protocol Chair:  Amol Narang, M.D.  
Version 7.0  May 19, 2020 
 
 
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NCT02017704 
Chemoradiation OR Brachytherapy for RECTal cancer 
 
Protocol Number: 
 
J1360 (NA_00082167) 
 
Coordinating Center:  
Johns Hopkins University 
 
Protocol Chair: 
 
Amol Narang, M.D. 
Sidney Kimmel Comprehensive Cancer Center 
Johns Hopkins University 
Weinberg Building 
401 N. Broadway, Suite 1440 
Baltimore, MD 21231 
Phone:  410-955-7390 
Fax:  410-502-1419 
Email: anarang2@jhmi.edu  
 
Co-Investigators: 
Susan Gearhart, M.D., Johns Hopkins University 
 
Laura D. Wood, M.D., Ph.D., Johns Hopkins University 
Nilofer Azad, M.D., Johns Hopkins University 
Luis Diaz, M.D., Johns Hopkins University 
Elizabeth Wick, M.D., Johns Hopkins University 
Sandy Fang, M.D., Johns Hopkins University 
Susannah Ellsworth, M.D., Johns Hopkins University 
Jonathan Efron, M.D., Johns Hopkins University 
Jennifer Barsky Reese, Ph.D., Johns Hopkins University 
Te Vuong, M.D., Segal Cancer Centre 
William Blackstock, M.D., Wake Forest Cancer Center 
Jerome Landry, M.D., Winship Cancer Institute, Emory University 
Stephen Greco, M.D., Johns Hopkins University 
Victoria Croog, M.D., Johns Hopkins University 
 
Statistician: 
Hao Wang, PhD 
 
Research Managers: 
Dana Kaplin 
Terry Caldwell 
 
Study Coordinators: 
 
James Huang 
 
 
 
 
Zhi Cheng 
 
 
 
 
Katie Lowe 
 
Research Nurses: 
 
Jessica Leitzel, R.N. 
 
 
 
 
                                                    Shirl DiPasquale, R.N. 
 
 
 
 
Danielle Wendler, R.N. 
 
Sponsor: 
 
 
Nucletron 
 
 
 


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Table of Contents 
 
SCHEMA...................................................................................................................................................................... 5 
1. 
HYPOTHESIS .................................................................................................................................................... 6 
2. 
ELIGIBILITY .................................................................................................................................................... 6 
3. 
BACKGROUND ................................................................................................................................................ 6 
3.1 
RATIONALE ................................................................................................................................................... 6 
3.2 
CORRELATIVE STUDIES ................................................................................................................................. 9 
3.3 
PRELIMINARY DATA ................................................................................................................................... 11 
4. 
OBJECTIVES .................................................................................................................................................. 16 
4.1 
PRIMARY OBJECTIVE .................................................................................................................................. 16 
4.2 
SECONDARY OBJECTIVES ............................................................................................................................ 16 
5. 
PARTICIPANT SELECTION ........................................................................................................................ 17 
5.1 
INCLUSION CRITERIA .................................................................................................................................. 17 
5.2 
EXCLUSION CRITERIA ................................................................................................................................. 17 
5.3 
INCLUSION OF WOMEN AND MINORITIES .................................................................................................... 18 
6. 
REGISTRATION PROCEDURES AND RANDOMIZATION .................................................................. 19 
6.1 
INFORMED CONSENT ................................................................................................................................... 19 
6.2 
SCREENING/BASELINE ASSESSMENTS AND PROCEDURES ........................................................................... 19 
6.3 
FIDUCIAL PLACEMENT ................................................................................................................................ 19 
6.4 
REGISTRATION PROCEDURES ...................................................................................................................... 19 
6.5 
RANDOMIZATION ........................................................................................................................................ 20 
7. 
TREATMENT PLAN AND DELIVERY....................................................................................................... 20 
7.1 
QUALITY ASSURANCE ................................................................................................................................. 20 
7.2 
ENDORECTAL BRACHYTHERAPY RADIATION THERAPY .............................................................................. 20 
7.3 
INTENSITY MODULATED RADIATION THERAPY AND CAPECITABINE .......................................................... 24 
7.4 
SURGERY .................................................................................................................................................... 30 
7.5 
FOLLOW-UP ASSESSMENTS ........................................................................................................................ 32 
7.5 
SUPPORTIVE CARE ...................................................................................................................................... 32 
7.6 
SUBJECT WITHDRAWAL/REMOVAL............................................................................................................. 33 
7.7 
COSTS ......................................................................................................................................................... 33 
8. 
COORDINATING CENTER .......................................................................................................................... 34 
8.1 
RESPONSIBILITIES ....................................................................................................................................... 34 
9. 
STUDY CALENDAR ...................................................................................................................................... 35 
9.1 
QUALITY OF LIFE SURVEY CALENDAR ....................................................................................................... 36 
10. 
MEASUREMENT OF EFFECT..................................................................................................................... 37 
10.1 
CENTRAL IMAGING REVIEW AND DETERMINING RESPONSE ....................................................................... 37 
10.2 
PATHOLOGIC EVALUATION OF TOTAL MESORECTAL SPECIMEN ................................................................. 37 
10.3 
QUALITY OF LIFE TOXICITY COMPARISON.................................................................................................. 38 
10.4 
MOLECULAR BIOLOGY CORRELATIVE STUDIES .......................................................................................... 40 
11. 
ADVERSE EVENT REPORTING ................................................................................................................. 41 
11.1 
GENERAL .................................................................................................................................................... 41 
11.2 
DEFINITIONS ............................................................................................................................................... 42 
11.3 
POTENTIAL ADVERSE EVENTS .................................................................................................................... 44 


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11.4 
ENDOSCOPY & MARKER IMPLANTATION .................................................................................................... 44 
11.5 
ENDORECTAL BRACHYTHERAPY RADIATION THERAPY .............................................................................. 44 
11.6 
INTENSITY MODULATED RADIATION THERAPY .......................................................................................... 45 
11.7 
SURGERY .................................................................................................................................................... 47 
11.8 
CHEMOTHERAPY ......................................................................................................................................... 47 
11.9 
RISKS OF BLOOD DRAWS ............................................................................................................................ 48 
11.10 
RISKS OF RADIOGRAPHIC IMAGING ........................................................................................................ 48 
11.11 
RISKS OF COMPLETING THE STUDY QUESTIONNAIRES ............................................................................. 48 
11.12 
REPORTING PROCEDURES ....................................................................................................................... 48 
12. 
DATA AND SAFETY MONITORING PLAN .............................................................................................. 49 
12.1 
DATA RECORDING ...................................................................................................................................... 49 
13. 
REGULATORY CONSIDERATIONS .......................................................................................................... 50 
13.1 
PROTOCOL REVIEW AND AMENDMENTS ..................................................................................................... 50 
13.2 
INFORMED CONSENT ................................................................................................................................... 50 
13.3 
ETHICS AND GCP ........................................................................................................................................ 50 
14. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 51 
14.1 
ENDPOINTS ................................................................................................................................................. 51 
14.2 
SAMPLE SIZE/ACCRUAL RATE .................................................................................................................... 51 
14.3 
EARLY STOPPING GUIDELINES .................................................................................................................... 52 
14.4 
ANALYSIS OF PRIMARY ENDPOINT.............................................................................................................. 52 
14.5 
ANALYSIS OF SECONDARY ENDPOINTS ....................................................................................................... 52 
REFERENCES: ......................................................................................................................................................... 54 
APPENDIX I: SKCCC DSMP I .............................................................................................................................. 61 
APPENDIX II: PARTICIPATING SITE GUIDELINES ........................................................................................ 62 
APPENDIX III: NEOADJUVANT ENDO-HDR QUALITY CRITERIA ........................................................................... 66 
APPENDIX IV: TUMOR REGRESSION DEFINITION ................................................................................................. 67 
APPENDIX V: QUALITY OF TME .......................................................................................................................... 68 
APPENDIX VI: INTRA-OPERATIVE DATA COLLECTION ......................................................................................... 69 
APPENDIX VI: QUALITY OF LIFE ASSESSMENTS ................................................................................................... 70 
APPENDIX VII: IMAGING TECHNIQUES/CENTRAL IMAGE REVIEW ....................................................................... 86 
APPENDIX VII: PERFORMANCE STATUS ............................................................................................................... 88 
APPENDIX IX: AJCC STAGING ............................................................................................................................. 89 
 


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Summary of Changes 
 
Protocol Revision 
Date 
Protocol Revision 
Description of 
Change 
Reason for Change 
August 30, 2013 
Version 1.0 
Original version 
Original release 
August 27th, 2014 
Version 2.0 
Adjusting Site Info 
Changing Gamma 
West PI 
March 25th, 2015 
Version 3.0 
Eligibility/Parameters 
Revision 
Accrual 
January 21, 2016 
Version 4.0 
Study Calendar 
Revision/Enrollment 
process/Eligibility 
Data Collection, 
scheduling, eligilbity 
clarification 
July 13, 2016 
Version 5.0 
Study Team updates 
on the cover page 
Changed Study Team 
November 11, 2019 
Version 6.0 
Study Team updates 
on the cover page 
Changed Study Team 
May 19, 2020 
Version 7.0 
Study Team updates 
on the cover page 
Changed Study Team 


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SCHEMA 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline studies to 
confirm eligibility 
ENROLLMENT/RANDOMIZATION 
(if eligibility is met, and knowledge of treatment 
arm is needed by clinic team) 
EUS/Fiducial 
placement 
ENROLLMENT/RANDOMIZATION 
 (if not already completed) 
 
Endo-HDR 
6.5Gy x 4 days 
5-FU (Cap) + RT 
50.4Gy/5.5 weeks 
TME 
FOLFOX x 12 Cycles 
TME 
FOLFOX x 12 Cycles 
Pre-Op follow-up 
Pre-Op Follow-up 
Yearly Follow-up 
Yearly Follow-up 
Rectal Cancer 
T2N1-2 or T3N0-2b 
<14 cm from A-V 
Negative iliac/Inguinal LN 
8-12 weeks 
8-12 weeks 


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1. HYPOTHESIS 
Pathologic complete response (pCR) is associated with improved survival and lower risk for 
distant metastases. Neoadjuvant Endo-HDR will increase pCR rates compared to concurrent 
chemoradiation (RT + Capecitabine).  We expect similar locoregional control, decreased 
treatment time (1 week as opposed to 6 weeks), improved sphincter preservation rates, and lower 
acute and chronic toxicity. 
2. ELIGIBILITY 
Patients with low rectal cancer who are candidates for endorectal brachytherapy (non-obstructing 
lesions which can be adequately treated with this technique will be eligible for the study).  Distal 
rectal tumors at 14 cm or less from the anal verge or rectosigmoid junction are included. Patients 
with T4 and/or presumed pathologic iliac/inguinal lymphadenopathy on PET/CT or MRI (>1.5 
cm in diameter or necrotic appearing) are excluded. 
3. BACKGROUND 
3.1 
Rationale 
Locally advanced rectal carcinoma continues to be a major oncologic problem in the 
United States with approximately 40,000 new cases diagnosed in 2012 For stage II/III 
rectal carcinoma, adjuvant chemoradiation (1-3) and total mesorectal excision  (TME) (4, 
5) represent the major treatment advances that have increased cure rates over the past 30 
years. 
 
In the setting of TME, a landmark phase III German trial of stage II/III rectal cancer 
patients established neoadjuvant 5FU-based chemoradiation (NCRT) as standard of care 
over the same regimen given post-operatively (6). The preoperative arm showed superior 
local control (6% vs. 13% p=0.006), a complete pathologic response of 8%, a higher rate 
of sphincter preservation and less grade 3 toxicity compared to post-operative treatment. 
However, disease-free and overall survival (76% versus 74%, respectively) were no 
different because of the high rate of distant metastasis occurring in over 1/3 of patients 
(5yr DM 36 vs 38%, p=0.84). Importantly, those attaining a pathologic complete 
response had a decreased rate of distant metastasis and improved disease-free survival. 
Drawbacks to the regimen include acute grade 3 or 4 toxicity in 27% of patients, low 
compliance rates with postoperative chemotherapy (27 – 50%), and an overall decline in 
anorectal function shown by long-term studies (6).  
 
Given the excellent locoregional control reported in TME surgical series, several trials 
have investigated whether certain patients may be spared preoperative radiotherapy (7-9). 
Two large randomized trials by Dutch and British investigators showed that a short 
preoperative course of hypofractionated EBRT (25 Gy in 5 fractions) followed by TME 
surgery decreased locoregional recurrence by 2/3 as compared to patients treated with 
TME surgery alone. In the Dutch trial, patients with mid and distal rectal cancers were 
most likely to benefit from radiotherapy.  In these patients, preoperative radiation was 
shown to decrease locoregional recurrence by 5-fold (10% to 2%); however, the 


J1360 CORRECT 
Protocol Chair:  Amol Narang, M.D.  
Version 7.0  May 19, 2020 
 
 
7 
 
hypofractionated preoperative EBRT regimen was associated with a significant increase 
in acute and chronic morbidity.  Indeed, the Dutch study revealed that irradiated patients, 
when compared to surgery alone, had more perineal wound healing problems after 
abdominoperineal resection (29% vs. 19%), worsening deterioration of anal sphincter 
dysfunction, and more severe long-term effects related to sexual functioning both in 
males (p=0.004) and females (p<0.002) (10-12). Additionally, colleagues have reported a 
consistent negative impact on bowel function in those patients undergoing sphincter 
preservation (13). In reviewing the long-term data of the Swedish short course 
preoperative EBRT rectal cancer trial, Birgisson also  reported a higher incidence of 
secondary tumors (9.5%) in patients treated with preoperative radiation when compared 
to patients having surgery alone (4.3%) (14). 
 
Modern approaches to address the risk of distant metastasis and poor compliance with 
adjuvant systemic chemotherapy (following NCRT) have incorporated newer effective 
chemotherapy agents earlier in the treatment protocol. For example, oxaliplatin has been 
one of the most widely studied agents as a result of its proven efficacy when combined 
with 5-fluorouracil and leucovorin (FOLFOX) both in the metastatic and adjuvant 
settings for colon cancer(15). Initial phase II studies with the addition of oxaliplatin to 
standard 5-FU based NCRT appeared to show improved pathologic complete response 
rates compared to standard NCRT.  However, two phase III trials clearly show that the 
addition of oxaliplatin during 5FU-based NCRT does not significantly improve 
pathologic complete response, locoregional control, distant metastasis or survival but 
does increase acute grade 3-4 toxicity by two to three-fold (16, 17).  
 
One approach to limit toxicity from external beam radiotherapy is the use of intensity 
modulated radiation therapy (IMRT).  IMRT can limit radiation dose to normal rectum 
(above and below the tumor) and surrounding organs at risk (OARs) such as bladder and 
sexual organs.  IMRT utilizes multiple beams of radiation to treat the rectal tumor plus a 
margin and limits dose to OARs. While IMRT decreases radiation dose to normal 
structures, it requires an additional 2-3 cm margin for microscopic extension (clinical 
treatment volume=CTV), set-up error, and rectal motion (planning treatment 
volume=PTV). Furthermore, IMRT still requires 5-6 weeks of radiation with concurrent 
chemotherapy,  is substantially more expensive than conformal radiation, and is 
especially prohibitive in countries where access to technology necessary for IMRT is 
limited (20).  Based on the preliminary results of RTOG 0822 and others, it still remains 
to be determined whether IMRT confers a statistically significant improvement in pCR, 
toxicity rates and QOL relative to standard NCRT. 
 
A novel approach to limit radiation toxicity is the use of high dose rate endorectal 
brachytherapy (Endo-HDR) (21). Endo-HDR involves the placement of a silicon 
multicatheter applicator within the rectum to deliver large doses to the rectal tumor and 
mesorectum with rapid dose fall off to the surrounding organs. An Iridium 192 high dose 
rate brachytherapy source attached to a wire is inserted into each catheter to deliver a 
high dose of radiation therapy the tumor. High dose rate brachytherapy has been well 
established in various malignancies (prostate, uterine, sarcoma, head and neck) to 
escalate radiation dose to the tumor over a short period of time while sparing normal 


J1360 CORRECT 
Protocol Chair:  Amol Narang, M.D.  
Version 7.0  May 19, 2020 
 
 
8 
 
tissue. Compared with NCRT and IMRT, Endo-HDR delivers treatment internally to the 
tumor without having to pass through surrounding normal tissue and organs. It requires 
smaller margins (CTV/PTV=~1 cm) on the tumor since the applicator is positioned under 
fiducial guidance over the tumor without need for a margin for organ motion allowing 
greater sparing of OARs (22). Furthermore, the area of the rectum exposed to high dose 
radiotherapy is surgically removed at the time of resection which further minimizes 
chronic toxicity. Important structures that may be spared include bone marrow, small 
bowel, bladder, the autonomic nerves, sexual organs, anal sphincter and skin. 
Considering that 1/3 of patients will develop metastases, limiting bone marrow toxicity 
may contribute to better compliance with systemic treatment and allow for a better 
treatment strategy to target systemic recurrence. Another distinct advantage of Endo-
HDR is the shortened treatment time (1 versus 6 weeks).  Endo-HDR therefore provides a 
major logistic advantage for patients who may benefit from neoadjuvant therapy but who 
are geographically distant from radiation centers, elderly, or medically infirmed. 
 
At the McGill University Health Center (MUHC), Vuong reported a phase II trial using 
high dose rate brachytherapy without concurrent chemotherapy to treat 285 (260 T3 
tumors, 7 T4 tumors, and 18 T2 tumors and 38% were N+) rectal cancer within 10 cm 
from the anal verge from 1998-2007. The median age was 69 years (range 42-90) (23). 
Patients received four fractions of 6.5 Gy (26 Gy total) HDR-BT treatments in one week 
followed by a 6-8 week period of downstaging prior to resection. Treatment planning was 
CT-based with MRI, ultrasound imaging and use of fiducial markers using radioopaque 
clips placed under direct endoscopic visualization with the tumor bed defined as any 
visible disease seen in at the primary site or mesorectal nodal deposits. Patients with node 
positive disease at the time of surgery received adjuvant chemotherapy and EBRT. At a 
median follow-up time of 54 months, the 5 year actuarial local recurrence rate is 5%, 
with a doubling of pathologic complete response compared to standard chemoradiation 
(27%), < 1%  grade 3-4 acute toxicity and no apparent increased long-term toxicity when 
compared to patients treated with TME alone. The disease-free survival is 65%, and the 
overall survival rate is 68% (23). Those patients attaining a pathologic complete response 
had improved survival and fewer distant metastasis. Grade 1-2 proctitis was noted in all 
patients starting 7–10 days after therapy and continuing until resection. While one patient 
experienced grade 3 toxicity, none had grade 4 proctitis. Surgical complications were 
limited to an anastomic leak rate of 10% and a perineal wound infection rate of 12% 
comparable to standard surgical experiences alone. Importantly, Endo-HDR did not 
compromise the pelvic bone marrow function and was not associated with hematologic 
toxicity. Based on these promising results, a current NCI Canada trial randomizes rectal 
cancer patients  treated with Endo-HDR followed by TME to either pre- vs. post-
operative FOLFOX. 
 
Although these are promising results supporting the use of Endo-HDR, a theoretical 
concern of using this treatment strategy to treat only the primary site and adjacent 
mesorectal nodes is the potential for increased pelvic nodal recurrence without elective 
treatment with external beam radiotherapy (24). Standard NCRT covers the internal iliac, 
perirectal lymph nodes, mesorectum, and primary tumor (25). Current radiation portals 
are derived largely from Gunderson and Sosin’s detailed study of the pattern of 


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recurrence after bluntly dissected rectal cancers. However, modern surgical series in 
patients treated without external beam radiation have shown  that the majority of pelvic 
failures occur locally in the anastomosis and presacral tumor bed and that the incidence 
of extramesorectal pelvic nodal failure is low both in overall incidence as well as an 
isolated source of failure (4, 26-28). Wiig, reporting on 100 cases of local recurrence 
after TME, concluded that all recurrences were within reach of the examining finger and 
at the tumor bed (26). In the same series, there was only one case of nodal recurrence in 
the lateral pelvic wall. In the Dutch TME referenced above, the rate of extramesorectal 
pelvic nodal failure was 1.6% in the TME alone arm versus 1.3% who received 
preoperative radiation therapy. Moreover, preoperative treatment of extramesorectal 
nodes with chemoradiation may not improve outcomes. In the MERCURY study, MRI-
based assessment of tumor regression and circumferential margin were prognostic for 
survival after neoadjuvant chemoradiation (29). Importantly, the presence of MRI 
detected extramesorectal lymphadenopathy did negatively impact disease-free survival; 
however, the use of neoadjuvant treatment did not alter the negative outcomes of iliac 
node positivity (29). 
3.2 
Correlative Studies 
3.2.1 FDG-PET 
The motivation for HDR brachytherapy in the treatment of rectal cancer is that a 
localized high dose rate gradient will improve pathologic complete response rates 
when compared to the homogeneous dose delivery of IMRT. While the high dose 
rate aspect will enable a much higher biological effectiveness to the targeted region, 
it is important to note that according to the linear-quadratic model, normal organs are 
more sensitive to the effects of high dose rate than tumors. This makes the 
localization of the dose delivery an issue of concern.  
 
In this situation, FDG-PET will be a valuable tool to monitor treatment effect on the 
primary tumor as it is believed to better correlate with tumor response than CT-based 
criteria (30). We will exploit this hypothesis by examining the relation between dose 
and response as measured by 18F-FDG uptake in 192Ir HDR brachytherapy of rectal 
cancer at the voxel level as well as for the whole tumor. This strategy exploits 
another emerging concept that a single mean absorbed dose value is rarely indicative 
of tumor response.  
 
The following sequence of events will take place (the first four are patient procedures 
and the last is a theoretical exercise): 1) an initial 18F-FDG PET/CT scan (Figure 
1a); 2) 4 treatments of HDR 192Ir brachytherapy designed to deliver a minimum of 26 
Gy total to every voxel of the defined tumor region (Figure 1b); 3) a second 18F-FDG 
PET scan 8 weeks after treatment (Figure 1c); 4) resection of the tumor; 5) a 
comparison of pathologic tumor response with radiation dose distributions. 
 
Consequently, the correlations we will be examining will be twofold: 1) the entire 
tumor and 2) the individual voxels. The whole tumor mean dose will be compared to 
the change in 18F-FDG uptake in the tumor region both in absolute and in relative 


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change. A similar approach holds for the voxelized data; however, voxelized data 
represents a challenge in dosimetry: the uncertainty inherent in the individual voxel 
absorbed dose outweighs its value. However, when large number of voxels are 
considered, such as those that constitute an entire organ or a binned ensemble, 
significant results can be obtained. This is often exploited in the form of dose volume 
histograms (DVHs). We will use both DVHs and binned results in our analyses. 
 
3.2.2 DNA Damage Response 
The effect of radiation on tumor cells is to cause irreversible injury to essential 
components of the cell. A commonly affected pathway is the DNA damage response 
pathway.  We wish to compare how Endo-HDR versus NCRT affects this pathway.  
To do this, we will examine well-described genetic alterations (VEGF/EFGR, p53, 
BRAF, KRAS, PIK3CA, γ-H2AX, and XRCC1).  We will determine whether 
particular mutations predict for pCR rates status post treatment.  We will also 
correlate our findings with overall and disease-free survival. 
 
3.2.3 Cancer Genome Sequencing to Determine Genetic Predictors of Response to Endo-
HDR and IMRT 
Whole cancer exome analysis will be performed on a subset of cases of strong 
responders and non-responders in an unbiased manner.  Twenty thousand genes will 
be interrogated using tumor samples and whole blood using the Agilent capture 
platform and the Illumina HiSeq2000.  Samples will be sequenced at a depth of 100-
200X and analysis of these results will take into account clinical response.  
Correlation with clinical and pathologic response to therapy, disease free survival 
and overall survival will be performed against all the somatic genetic alterations 
found in each subset (32). 
 
3.2.5 The role of infectious and inflammatory processes in colon carcinogenesis is of 
intense interest since the colon is colonized with ~1012-13 commensal bacteria with 
the potential to induce inflammatory processes if colonic epithelial homeostasis is 
disrupted. The importance of inflammation in CRC is demonstrated by the dramatic 
increase in incidence among individuals with Inflammatory Bowel Disease (IBD). 
Bacterial initiators and promoters of immunologically driven CRC have long been 
proposed. Supportive human epidemiologic data show that migrating populations 
adopt the cancer risk of the region to which they relocate. Over time, the 
investigative focus has been on either mutagen production by colonic bacteria or 
their conversion of dietary procarcinogens into DNA-damaging molecules. Despite 
considerable effort, no direct links between the metabolic activities of bacteria and 
sporadic CRC are established. To date, the strongest, yet limited, evidence suggesting 
that commensal microbiota contribute to CRC pathogenesis derive from select, 
usually immune, gene knockout murine models in which the incidence of colon 
tumors usually decreases under germ-free conditions. The idea that the microbiome 
structure confers disease potential is supported by data, for example, indicating that 
murine colitis or disease phenotypes are transmissible through the microbiome. In 
2011, we initiated a project at Johns Hopkins in which primary, untreated CRC 
tumors along with flanking normal colon tissue from surgical specimens was 


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collected for microbial analysis. Microbial analysis included structural microbiology, 
classic anaerobic microbiology and deep sequencing of the tumor or normal tissue 
(mucosal)-associated microbiota. This project has yielded, to date a critical 
observations. In right CRCs examined to date, a marked biofilm is associated with 
the tumors and is also present on at least 40% of flanking normal tissues from the 
same patients. In contrast, no biofilms are detected on any left CRC tumors or on 
flanking normal colon tissues. These data suggest the microbial associations of right 
vs. left-sided CRC are distinct. Sequencing analyses have revealed trends to 
differences in specific microbial associations in right and left CRC. Left sided CRC 
analyzed to date have been from the descending and rectosigmoid region because 
most rectal cancer at JHH is treated before surgery with radiation and chemotherapy, 
both of which may modulate the microbiome, we have little information on microbial 
associations of rectal cancer. In conjunction with the endorectal brachytherapy trial 
for treatment of rectal cancer, we will collect 2 additional biopsies (tumor and 
normal) during the pre-treatment endoscopy (standard of care in current protocol). 
Biopsies are currently being collected for other correlative studies during this 
endoscopy and additional biopsies will not be taken if it interferes with patient care. 
Tissue will be snap frozen and used for microbial sequencing. Results will be 
analyzed in conjunction with ongoing CRC microbial studies (evaluations of right 
and left colon cancer) underway at JHH as well as correlative studies (tumor 
genetics) being conducted as part of the endorectal brachytherapy trial.  
 
3.3 
Preliminary Data 
In order to accurately quantify the effects of a) dose rate and b) heterogeneity in the 
normal organs and tumors and consequently the relative merits and potential of HDR 
brachytherapy as an adjunct for rectal cancer treatment, we will use dose volume 
histograms (DVHs) for all sensitive normal organs as well as the tumors and compare the 
DVHs to the DVHs from the IMRT treatment plans (performed on patient diagnostic 
scans). In order to compare dose values from different modalities, brachytherapy and 
IMRT external beam therapy, a conversion based on radiobiological modeling and the 
linear-quadratic equation is used. The different voxel doses are converted to the 
biological effective dose (BED) (41, 42) and from there to equivalent 180-cGy fractions 
(43) used in the IMRT plan. 
The formula for the biological equivalent dose (BED) is:
 








/
/
1
N
D
D
BED
  
where D is the total absorbed dose, N is the number of fractions (4 for the HDR 
brachytherapy; 28 for the IMRT plan) and alpha and beta are the radiobiological 
parameters for the linear-quadratic model of cell kill.  
 
The process of conversion to 180-cGy equivalent dose takes into account the higher dose 
rate in HDR. Accurate, detailed absorbed dose calculations are useful only to the extent 
that they are biologically relevant and easily interpretable. The uniformity (or lack 
thereof) of absorbed dose distributions and their biological implications has been 
examined intensively, primarily in animal studies (44-46). The equivalent uniform dose 


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(EUD) model converts the spatially varying absorbed dose distribution into an equivalent 
uniform absorbed dose value that would yield a biological response similar to the one 
expected from the original dose distribution. This provides a single value that may be 
used to compare different dose distributions (43, 47, 48) and may correlate to single 
tumor response values rather than the mean absorbed dose. This EUD value is another 
example of how voxelized data may be grouped to provide more biologically relevant 
information at a larger scale.  
 
 
Figure 1a. 
Figure 1b. 
Figure 1c. 
Figure 1. Illustration of dose-response as measured by 18F-FDG uptake imaged using a PET scanner. 
Figure 1a shows the PET scan uptake prior to brachytherapy; Figure 1b shows the dose distribution (bright 
spot) as well as the tumor target volume (in red). Figure 1c is the post HDR therapy PET scan. All images 
are overlaid on the planning CT.  
 


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Patient 
AD 
ADeq 
EUD 
Change in PET  R2 
 
(Gy) 
(Gy) 
(Gy) 
 
 
ER001 
41.0 
86.5 
34.8 
71.9 
0.82 
ER003 
51.6 
125.1 
44.7 
26.5 
0.18 
ER004 
51.1 
124.6 
32.7 
43.7 
0.89 
ER005 
51.0 
126.7 
30.4 
20.3 
0.82 
ER006 
49.7 
121.4 
25.3 
45.8 
0.70 
 
Table 1. Dose and response results for the planning tumor volume for five patients. AD is the average 
absorbed dose value, ADeq is the average in 180 cGy-fraction equivalent absorbed dose. EUD is the 
equivalent uniform dose. Change in PET is the total relative difference in PET uptake (absolute), while the 
R2 is for the fit to the binned data (see Figure 1b).  
 
In addition, patients will be evaluated by the PERCIST criteria as follows: 
(PET Response Criteria in Solid Tumors) 
 
Two key measurements performed in PERCIST 1.0 analyses are: 
 
 
 
Baseline Lesion Threshold 
 
It is calculated using the mean and standard deviation (in units of SUL-
Standardized uptake value adjusted for lean body mass) of a 3cm diameter VOI 
placed in the right lobe of the liver. 
 
Disease Threshold = (1.5 x Livermean) + (2 x Liversd) 
Figure 2a. 
Figure 2b. 
Figure 2. Dose and response results for the planning tumor volume for five patients. AD is the average 
absorbed dose value, ADeq is the average in 180 cGy-fraction equivalent absorbed dose. EUD is the 
equivalent uniform dose. Change in PET is the total relative difference in PET uptake (absolute), while the 
R2 is for the fit to the binned data (see Figure 1b).   


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Target Lesion Identification 
 
It is defined as the hottest single tumor lesions (in SUL) of maximal 1cc volume 
VOI in tumor (SUL PEAK) greater than calculated threshold of lesion 
detectability. 
 
For each study, the CAD system: 
 
Measured normal reference hepatic tissue using an automated algorithm, 
recording the mean and standard deviation of a 3cm VOI placed within the 
imaging study volume, and calculating the disease threshold as defined by 
PERCIST 1.0. 
 
Detected and statistically characterized lesion targets. Lesions targets were 
screened for false-positives and then ranked according to PEAK-SUL. The 
lesion with the hottest PEAK-SUL measurement was designated as the primary 
lesion. 
3.3.1 Preliminary Clinicopathologic Comparison of Endo-HDR with Other Modalities 
An initial 9 patients have been enrolled in our prospective Endo-HDR pilot study at 
Johns Hopkins University (ClinicalTrials.gov Identifier: NCT01226979). This is the 
first prospective study evaluating Endo-HDR in the U.S. All 8 evaluable patients had 
tumors <12 cm from the anal verge and no clinical/radiographic suspicious 
lymphadenopathy outside of the mesorectum (T2-T3, N0-N1). All patients had NCI 
CTCAE toxicity assessments, MRI, PET/CT, and CEA pre/post-Endo-HDR. 
RECIST/PERCIST criteria were used to assess response. Surgical specimens were 
reviewed by a single pathologist. All patients were margin negative and 8 had 
sphincter preserving surgery (one patient chose to have APR due to poor function 
prior to treatment). Three of 9 patients (33%) had a pCR of their primary tumors. 
Toxicity assessments showed only 1 patient with temporary grade 3 proctitis 
following Endo-HDR. All other toxicities were grade 2 or less, consisting of proctitis 
and pain managed conservatively. 
 
 
We have compared surgical specimens of patients treated with endorectal versus 
chemoradiation with IMRT or 3-dimensional conformal therapy (49).  Patients 
treated with endorectal brachytherapy showed greater treatment ulceration effect on 
the epithelium, greater hypertrophy of the submucosal rather than adventitial blood 
vessels and fewer serosal adhesions compared to external beam radiation techniques. 
See figures below. 
 


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Figure 3. Representative H&E stained histopathologic sections at 4X magnification from patients who 
exhibited a complete pathologic response to Endo-HDR (a-e) and conventional external beam 
radiation (f-j). All images are taken from the region of the rectal wall where the tumor was located 
prior to neoadjuvant therapy. All insets are shown at 20X magnification. First Row – At the mucosa, 
extensive ulceration (solid arrows) is apparent after Endo-HDR (a), while the mucosa remains intact 
(solid arrows) after conventional CRT (f). Hyalinization of the lamina propria (asterisks) is also 
evident after Endo-HDR (a). Second Row – In the submucosa, marked hypertrophy and sclerosis of 
vessel walls can be seen following Endo-HDR (b), while only slight hypertrophy of vessel walls is 
seen after conventional CRT (g). Third Row – Within the muscularis propria, the more superficial 
interna layer can be seen to exhibit degeneration and atrophy after Endo-HDR while the externa layer 
remains largely intact (c); in a contrary fashion, following conventional CRT, it is the externa layer 
that exhibits more prominent degeneration compared to the interna (h). Fourth Row – At the level of 
the subserosa, vessel walls appear normal in patients treated with Endo-HDR (d), but distinctly 
hypertrophied in patients treated with conventional CRT (i). Fifth Row - The serosa demonstrates few 
adhesions (asterisk) after treatment with Endo-HDR (e), in contrast to the extensive adhesions 
(asterisks) present after treatment with conventional CRT (j). 
 


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We propose comparing Endo-HDR versus standard NCRT (IMRT) for stage II/III 
low rectal cancer (<14 cm from the anal verge). We have focused on patients with 
distal rectal carcinomas and include patients likely to undergo an APR as they are at 
highest risk for local failure after TME and most would be excluded in the current 
national PROSPECT trial. We have also incorporated staging FDG-PET/CT and 
MRI to exclude any patients with radiographic evidence of pathologic inguinal or 
iliac lymphadenopathy (defined as >1.5 cm, necrotic on MRI as detailed in the 
MERCURY study, or suspicious on PET/CT) (29). 
 
4. OBJECTIVES 
4.1 
Primary Objective 
Determine whether Endo-HDR improves pathologic complete response rates when 
compared to IMRT and capecitabine. 
4.2 
Secondary Objectives 
 Test whether clinical response based on functional imaging (PET, MRI) pre/post 
radiation (Endo-HDR vs. CRT) predicts for pathologic complete response. 
 Utilize preoperative imaging response rates and clinical exam to determine whether 
Endo-HDR results in improved sphincter preservation rates when compared to CRT. 
 Determine whether tumor (VEGF/EGFR status) and blood predict for pathologic 
response following neoadjuvant Endo-HDR vs. CRT. 
 Compare acute and long-term toxicity as well as quality of life for both Endo-HDR 
and CRT. 
 Compare locoregional control, distant metastasis and overall survival for both Endo-
HDR and CRT. 
 


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5. PARTICIPANT SELECTION 
5.1 
Inclusion Criteria 
5.1.1 Histologically confirmed adenocarcinoma of the rectum 
5.1.2 T2N1-2 or T3N0-2b tumors at ≤ 14 cm from the A-V margin (below the peritoneal 
reflection) or the rectosigmoid junction. 
5.1.3 Tumors with a lumen sufficient to allow the positioning of the rectal applicator 
(standard probe/scope) confirmed by the treating physician.  
5.1.4 Tumors of less than 4 cm thickness from the rectal mucosa documented at the time of 
staging images 
5.1.5 Patients should be suitable candidates for surgery and chemotherapy 
5.1.6 ECOG/WHO performance status 0-1 
5.1.7 Patients must be 18 years or older 
5.1.8 No previous history of pelvic radiation 
5.1.9 Patients must have acceptable organ and marrow function as defined below: 
- 
Absolute Neutrophil Count ≥ 1.5 x 109/L 
- 
Platelets ≥ 100 x 109/L. 
- 
Serum creatinine ≤ 1.5 x ULN 
- 
Bilirubin ≤ 1.5 x ULN 
- 
ALT or AST ≤ 2.5 x ULN 
5.1.10 Non pregnant, non-breast feeding females under active contraception 
5.1.11 Ability to understand and willingness to sign a written informed consent document.  
  
5.2 
Exclusion Criteria 
5.2.1 Evidence of signet ring involvement on histology 
5.2.2 Evidence of necrotic or > 1.5 cm in diameter pelvic (iliac/inguinal) nodes 
5.2.3 Evidence of distant metastatic disease 
5.2.4 Evidence of sphincter invasion on MRI 
5.2.5 Prior history of radiation to the pelvis 


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5.2.6 Prior malignancy except for adequately treated basal cell or squamous cell skin 
cancer, cervical carcinoma in situ, DCIS, or other cancer from which the patient has 
been disease free for at least 3 years 
5.2.7 Presence of multiple small bowel loops trapped within the immediate tumor bed (post 
hysterectomy or prostatectomy). 
5.2.8 Use of any investigational agent within the 4 weeks preceding enrollment 
5.2.9 Previous exposure to chemotherapy for rectal cancer 
5.2.10 Uncontrolled intercurrent illness including but not limited to, ongoing or active 
infections (or infections requiring systemic treatment), symptomatic congestive heart 
failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements 
5.2.11 Pregnant and breastfeeding women are excluded, as well as women of child-bearing 
potential who are unwilling or unable to use an acceptable method of birth control 
(hormonal or barrier method of birth control; abstinence) to avoid pregnancy for the 
duration of the study. Should a woman become pregnant or suspect she is pregnant 
while participating in this study she should inform her treating physician 
immediately. 
5.2.12 Women who are not post-menopausal and have a positive urine or serum pregnancy 
test or refuse to take a pregnancy test. 
5.2.13 Contraindication for safe MRI, implants, or other conditions that interfere with 
imaging required for the study (e.g., pacemaker or non-MRI compatible hip 
prostheses). Note: Subjects with bilateral hip implants are not eligible for the study. 
Subjects with a unilateral hip implant may be eligible assuming the implant is MRI 
compatible and does not present artifact on MRI in the areas of interest. 
5.2.14 Subject is pacemaker dependent. 
 
5.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 


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6. REGISTRATION PROCEDURES AND RANDOMIZATION 
6.1 
Informed Consent 
All subjects considered from enrollment in the study must complete an IRB approved 
informed consent prior to any study-specific procedures being performed (Section 13.2). 
6.2 
Screening/Baseline Assessments and Procedures 
The following procedures and assessments will be performed within 6 weeks prior to the 
initiation of radiation therapy. 
 Demographic information 
 Medical history and physical examination 
 Performance status 
 Concomitant medications 
 Fiducial marker placement (within 3 weeks of start) 
 Research biopsies of tumor and adjacent normal tissue and blood samples 
(optional) 
 FDG-PET/CT 
 Pelvic MRI 
 CBC w/ diff, CMP, CEA, and testosterone for male participants 
 Quality of life assessments 
 Assessment of baseline symptoms 
 Pregnancy test for women of child-bearing potential 
6.3 
Fiducial Placement 
Endoscopic evaluation will be performed by the surgical team to assess the tumor, 
ensure adequate lumen for probe placement, and to mark the tumor with MRI 
compatible gold fiducials (markers) for guidance during Endo-HDR and CRT 
treatment planning. Fiducials should be placed above and below the tumor and the 
tumor margins should also be marked with tattoo. The recommended fiducials to be 
used are Visicoil™ (0.75mm x 1cm) image markers. When possible, dye should be 
placed during EUS in the mucosa to demarcate the superior, inferior, and lateral aspects 
of the tumor. 
 
At the time of endoscopic assessment, tissue biopsies of the tumor may be obtained for 
correlative studies. After completion of clinical and radiological evaluations under direct 
rectoscopy, radio-opaque markers are placed to identify the proximal and distal margins 
of the tumor for subsequent positioning quality control of simulation and treatment 
applications. 
6.4 
Registration Procedures 
Eligible patients will be entered on study centrally at the Johns Hopkins Hospital by the 
Study Coordinator. 
 


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To register a patient, the following documents should be completed by the research nurse 
or data manager and sent to the Study Coordinator. 
 
Source documentation verifying eligibility 
 
Eligibility checklist 
 
Signed patient consent form 
If the patient is deemed eligible for the study, the Study Coordinator will register the 
patient and assign a study number. 
6.5 
Randomization 
Eligible subjects will be randomly assigned in a 2:1 ratio to receive either endorectal 
brachytherapy or IMRT using the method of randomly permuted blocks in strata defined 
by study site. The patient may be enrolled and randomized before the endoscopic 
ultrasound and fiducial placement if all eleiglibility requirements are met. A master list of 
randomization assignments will be made by the protocol statistician, and will be 
delivered to the lead site by email or facsimile report. 
 
7. TREATMENT PLAN AND DELIVERY 
7.1 
Quality Assurance 
Tumor volumes and radiation plans for Endo-HDR, 3D-conformal radiation, and 
IMRT will be reviewed.  Dr. Vuong and Dr. Narang will review the first 5 endorectal 
plans at each institution. The first 3 3D-conformal and/or IMRT plans from each 
institution will be reviewed by either Dr. Narang, Dr. Hu, or Dr. Biagioli. All plans 
(Endo-HDR and IMRT) will be centrally reviewed by Dr. Narang, Dr. Hu, or Dr. 
Biagioli after completion of the study. 
7.2 
Endorectal Brachytherapy Radiation Therapy 
7.2.1 Endorectal Brachytherapy Radiation Therapy 
 
At the initial assessment, the surgeon will be asked to determine the likelihood of 
sphincter preservation. Endo-HDR is an outpatient procedure. 
 
Patients will be treated with a daily dose of 6.5 Gy over four consecutive days for a 
total of 26 Gy. To administer Endo-HDR, patients will be placed in the lateral 
decubitus position to insert the endorectal applicator and then maneuvered into the 
supine position. Once in place, the applicator is secured to the plate/holder and an 
anal BB is placed at the anal verge. Dummy wires are inserted into the applicator and 
the patient is scanned using CT (2 mm slices). The radio-opaque (MRI safe-optimal) 
markers will guide application of the endorectal probe and assist with tumor 
delineation during IMRT treatment. For Endo-HDR, RT dose will be prescribed to 
the tumor radial margins or mesorectal node, whichever is greater not to exceed 3.5 
cm from the mucosal surface. Prescribed dose will include a 1 cm CTV/PTV 
proximal and distal expansion excluding anal sphincter distally. However, when the 
GTV is close to the sphincter, the CTV should not be expanded distally into the 


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sphincter (treat GTV only).  The endorectal applicator is flexible, with nine-channels 
using a high dose-rate remote after-loading system. Standard radiation procedures 
will be followed during Endo-HDR as outlined in the protocol. QOL will be assessed 
throughout the treatment process (see calendar). Endoscopic endorectal ultrasound 
(EUS) is obtained for tumor staging and magnetic resonance imaging (MRI) of the 
pelvis is used for tumor measurements (length and bulk evaluation). 
 
7.2.2 Endorectal Brachytherapy Equipment 
The treatment is delivered using a recognized endorectal applicator (Oncosmart, 
Nucletron) consisting of a central flexible tube with 8 catheters arranged around the 
circumference of a central tube. Treatment planning is performed using CT 
simulation. A hydraulic locking clamp mounted on a Plexiglas plate is manufactured 
for immobilization during the CT simulation. High dose rate brachytherapy is 
delivered using a Nucletron microselectron HDR (iridium-192 source).  
 
7.2.3 Endorectal Brachytherapy Simulation 
The 3D treatment planning process is carried out as follows. Prior to CT simulation, 
an initial anterio-posterior (AP) scout view of the patient lying in supine position is 
done in order to visualize the endorectal radio-opaque markers. The endorectal 
applicator is introduced using lubrication with the patient lying in the lateral 
decubitus position. The patient is then repositioned in the supine position and a 
Plexiglas plate with the mounted hydraulic locking clamp is slid under the patient’s 
pelvis and the Oncosmart intracavitary mold is latched onto the hydraulic locking 
clamp. Repeated AP and lateral scout views are then taken and examined. When 
necessary, adjustments are made to the cephalic orientations of the applicator relative 
to the radio-opaque marker locations. The tip of the applicator will be positioned at 
least 2 cm beyond the proximal extent of tumor. With the applicator in the optimal 
position, CT scanning is performed using a slice thickness and separation of 2.5 to 5 
mm to scan the area, which extends from the upper third thigh to a few cm above the 
tip of the endorectal applicator. Following the CT, the acquired images are sent a 
dedicated virtual simulation image processing workstation. Contoured tumor, 
catheters and endorectal markers are incorporated into digitally reconstructed 
radiographs (DRRs) or digitally composite radiographs (DCRs) to enhance 
selectively visualization and use as references for daily treatment. 
 
7.2.4 Endorectal Brachytherapy 3D Treatment Planning 
The tumor volume is defined as the (gross tumor volume=GTV).  The GTV plus 
additional intramesorectal extension is defined as the clinical target volume=CTV) 
(Figure 4).  Adjacent normal tissues will also be contoured.  The normal rectal 
volume is the volume confined to within 5 mm of the perimeter of the balloon that 
did not extend beyond 1 cm of the superior and inferior margins of the target.  When 
a balloon is not used, the normal rectum volume will be confined to the normal 
rectum (non-CTV) within 5 mm of the applicator.  The percentage of the CTV 
covered by 100% and 150% of Dref (V100 and V150), and the minimum dose 
received by 90% of the CTV (D90) will be calculated. The mean dose (Dmean) to 
normal tissues, inclusive of bladder, femoral heads, bone marrow, uterus, vagina, 


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prostate, penile bulb will also be calculated and included in the dose volume 
histogram. Bone marrow will be defined by contouring all osseous structures from 
the L4/L5 interspace through the sacrum, pelvis, and proximal femurs to the inferior 
aspect of the inferior pubic rami. The other normal structures will be defined in 
accordance with the RTOG male and female atlas guidelines (see Section 7.2.9).  In 
addition, the minimum dose to the hotest 1, 2, and 5 cm3 (D1cc, D2cc, and D5cc) of 
the normal structures will be calculated to examine anatomic heterogeneity effects. 
The doses are expressed as a percentage of Dref.  We will confirm that 100% of the 
CTV volume is covered by the 95% isodose line. Any visible perirectal lymph nodes 
seen on imaging will be included in the treatment volume however other mesorectal 
lymph nodes are not always included as it is assumed these will be removed by the 
TME.  As a general rule, any lymph node deposits located within 0.5 and 1 cm from 
the target CTV will receive 75% and 50% of the prescribed dose.  Endorectal 
markers as well as the first dwell position are incorporated into digitally 
reconstructed radiographs for use as a reference for the daily treatments. The digitally 
reconstructed radiographs will be created with the reconstruction plane set at the 
level of the applicator so that the ruler can be used for distance measurements 
between radio-opaque markers and the first dwell position of the applicator.  Dwell 
positions are determined with respect to the extent of the contoured target. Catheters 
are loaded in a differential manner so that only those in close proximity with the 
tumor contain active source dwell positions. After the source position determination, 
CT-aided brachytherapy treatment planning is carried out to fully conform the dose 
distribution to the target, and to limit dose as much as possible to immediately 
adjacent tissues beyond the rectal wall.  
 
 
Figure 4. Fusion of Endo-HDR CT simulation with a) MRI and b) PET/CT imaging. 
 
 
7.2.5 The Differential Source Positioning Technique 
Source positions for brachytherapy are determined with respect to the contoured 
tumor. Catheters are loaded in a differential manner so that only those in direct 
contact with the tumor contain active source dwell positions. Following the source 
position determination, CT-aided brachytherapy treatment planning is carried out so 
as to optimize fully the dose to the tumor, while limiting the dose to immediate 
adjacent tissues beyond the rectal wall. Isodose distributions were generated by 
Oncentra software (Nucletron USA), see dose distribution above (Figure 4b). 
 


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7.2.6 Treatment Delivery 
With the patient in lithotomy position, individually marked tungsten dummies are 
inserted into selected channels. Prior to each treatment, AP and lateral daily check 
films are obtained and compared to either AP and lateral scout films or treatment 
planning DRRs to visualize the endorectal applicator position and orientation 
according to the radio-opaque endorectal markers and bony landmarks. These pre-
treatment check films aid in determining both the depth and rotation of the endorectal 
applicator with respect to the intended position, as determined from the CT-
simulation. The channel orientation is determined by the position of the dummies on 
check films. In the event that plain films are not available prior to a brachytherapy 
fraction, it is permissible to evaluate the brachytherapy applicator and plan on CT. 
 
7.2.7 Dose Prescription 
A total dose of 26 Gy in 4 daily fractions of 6.5 Gy will be prescribed at the CTV, 
defined as the GTV and intramesorectal deposits seen on the pre-staging MRI. The 
dose will be delivered with a differential channel loading of the endorectal applicator. 
 
7.2.8 Dose Modifications 
Every effort will be made to administer the entire radiation treatment to participants.  
Every effort will be made to limit the dose to the bladder, femoral heads, small 
bowel, vagina, uterus, and/or penile bulb.   
 
7.2.9 Organs at Risk (OAR) 
The following normal tissues of interest will be contoured and the dose to each 
recorded according to the RTOG male and female atlas guidelines: 
http://www.rtog.org/CoreLab/ContouringAtlases/MaleRTOGNormalPelvisAtlas.aspx 
http://www.rtog.org/CoreLab/ContouringAtlases/FemaleRTOGNormalPelvisAtlas.as
px 
 
No part of these normal structures will be permitted to receive more than the 
prescription dose of 26 Gy (6.5 Gy x 4 fractions). 
 All patients:  
 Small bowel, large bowel, sigmoid colon 
 Bladder 
 Femoral Heads 
 Anal sphincter 
 Female patients: 
 Vagina  
 Uterus 
 Male patients: 
 Prostate 
 Seminal Vesicles 
 Penile bulb 


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Structure 
0.1 cc 
2 cc 
Anus* 
6.5 Gy 
4.8 Gy 
Penile Bulb 
5.9 Gy 
4.8 Gy 
Bladder 
7.0 Gy 
 
Sigmoid 
6.5 Gy 
 
Table 2. Dose Constraints for Endorectal Brachytherapy Treatment 
*When the tumor approaches but does not involve the anal sphincters the dose to the anus may exceed 
the above constraints.  Every effort should be made to limit this dose as much as possible. 
  
7.3 
Intensity Modulated Radiation Therapy and Capecitabine 
7.3.1 IMRT Planning 
External radiotherapy will be based on contouring guidelines from the RTOG atlas 
and Radiation Therapy Oncology Group (RTOG 0822) with modifications described 
below. 
 
Patients will undergo CT (required) and MRI simulation (optional) in the supine 
position with concurrent administration of IV and oral contrast.  (IV contrast may be 
omitted for patients with contrast allergy or another contraindication.)  The bladder 
should be full.  A custom immobilization device such as a vac-loc bag or alpha cradle 
should be used to ensure consistent setup.  An anal BB marker should also be placed 
at the time of simulation.  
7.3.1.1 
Gross Tumor Evaluation for IMRT Treatment Planning 
 
GTV Primary Tumor  
 
Increased SUV on PET/CT will define inferior and superior aspect of tumor. 
Use bony anatomy to help with orientation if PET cannot be fused to planning 
CT.  
 
Use MRI to better define the anterior and posterior borders of the tumor. 
Again use Bony landmarks to help with orientation. 
 
GTV Involved Nodes  
 
Contour GTV for mesorectal lymph nodes which are >1cm and adjacent to 
the tumor (<1 cm), show enhancement on PET or MRI and/or have anatomic 
abnormalities suspicious for tumor involvement (based on MERCURY 
study). 
 
CTV for gross disease (per RTOG 0822) 
 
Primary tumor CTV = Primary Tumor GTV +1.5cm radially and 2.5cm 
craniocaudally 
 
Involved Node CTV = Involved Node GTV + 1.5cm symmetrical expansion 
7.3.1.2 
Clinical Treat. Vol. (CTV) & Planning Treat. Vol. (PTV) for IMRT 
The RTOG Anorectal Contouring Guidelines will be used to guide treatment 
planning for patients in the IMRT arm of this study (50).  Two PTVs will be created 
according to these guidelines.  PTV-Initial will consist of CTVA plus margin, 


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including pelvic lymph nodes, the mesorectum, and the primary tumor plus margin 
and will receive 45 Gy in 25 1.8-Gy fractions.  PTV-Conedown will include the 
rectal primary tumor plus margin and will receive 5.4 Gy in 3 1.8-Gy fractions.  The 
RTOG contouring guidelines for creating target volumes are summarized below. 
 
PTV-Initial 
CTVA consists of the following areas that must always be treated in rectal cancer 
and will be uniformly expanded by 0.5 cm to create PTV-Initial.  This volume will 
receive 45 Gy (1.8 Gy x 25).  
  
 Superior border: The recommended superior extent of the peri-rectal component 
of CTVA was at whichever is more cephalad: the rectosigmoid junction or 2 cm 
proximal to the superior extent of macroscopic disease in the rectum/peri-rectal 
nodes.  This defines how much of the distal large bowel should be within CTVA.  
The most cephalad extent of CTVA will be higher than the peri-rectal 
component, in order to properly cover the internal iliac and pre-sacral regions.  
The most cephalad aspect of CTVA should be where the common iliac vessels 
bifurcate into external/internal iliacs (approximate boney landmark: sacral 
promontory). 
 
 Inferior border: Minimum 2 cm caudal to gross disease including coverage of 
entire mesorectum to the pelvic floor. Unless radiographic evidence of extension 
to ischiorectal fossa, CTVA need not extend through the levator muscles. For 
very advanced anal or rectal cancers, extending through the mesorectum or the 
levators, the group’s recommendation is to add ~1-2 cm margin up to bone 
wherever the cancer extends beyond the usual compartments.  An MRI and/or 
PET/CT scan is strongly recommended in such cases.  
  
CTVA will also include the following structures:  
o Iliac Lymphatic CTV= Internal iliac vessels + 1.0 cm symmetrical 
expansion.  
o Presacral Lymphatic CTV = 8mm anterior to anterior border of sacral 
bone (extending from S1-S5) 
o Mesorectal and perirectal lymphatic CTV 
o Posterior border: anterior border of the sacrum and gluteus maximus 
o Lateral border: Ileum, piriformis and obturator muscles 
o Anterior border should overlap 1cm into the bladder, vagina or prostate. 
o In the mid pelvis, this volume should include at least the posterior portion 
of the internal obturator vessels (which lie between the external and 
internal iliacs in the mid pelvis).  
 
PTV-Conedown 
CTV-B consists of the following structures that require a boost dose of radiation.  A 
0.5 cm uniform margin will be placed around the following structures to create PTV-
Conedown. This volume will receive 5.4 Gy (1.8 Gy x 3).  
o Primary tumor GTV 


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o Involved nodal GTV (if present) 
o Presacral CTV (see above)   
 
References: 
RTOG Anorectal Contouring Atlas 
http://www.rtog.org/LinkClick.aspx?fileticket=DgflROvKQ6w%3d&tabid=231 
RTOG 0822 Protocol, Section 6 (Radiation Therapy) 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?action=openFile
&FileID=4663 
7.3.1.3 
Planning Constraints for IMRT Plans 
7.3.1.3.1 Normal Tissue Dose Constraints 
The following normal structures must be contoured for each IMRT treatment plan: 
o Small bowel, large bowel, sigmoid colon (contour up to 1cm above PTV) 
 ≤ 180 cc above 35 Gy 
 ≤ 100 cc above 40 Gy 
 ≤ 65 cc above 45 Gy 
 No small bowel volume should reach 50 Gy 
o Bladder 
 ≤ 40% above 40 Gy 
 ≤ 15% above 45 Gy 
 No bladder volume should reach 50 Gy 
o Femoral Heads 
 ≤ 40% above 40 Gy 
o Contour and Limit Dose as much as possible to the following structures: 
 Anal Sphincter 
 Female: 
 Uterus 
 Vagina 
 Male: 
 Prostate 
 Seminal Vesicles 
7.3.1.3.2 PTV Planning Dose-Volume Constraints 
o ≥ 98% of PTV receives at least 93% of planned dose 
o ≤  10% of PTV receives ≥ 105% of prescribed dose 
o ≤  5% of PTV receives ≥ 110% of prescribed dose 
o None of the PTV is to receive ≥ 115% of prescribed dose 
7.3.2 Image Guided Radiation Therapy (IGRT) for IMRT Plans 
IGRT is optional in this trial.  If used, IGRT should consist of daily CBCT or MVCT 
to bony pelvis with shifts made on kV port films to ensure that rectal markers and 
pelvis lymph nodes are covered with an adequate margin. 


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7.3.3 3-D Conformal Radiation Therapy (3-D CRT) 
3-D CRT and/or tomotherapy 3-D plans will be permitted on this protocol for 
patients who have difficulty obtaining insurance coverage or have other issues that 
preclude the use of IMRT, although IMRT is preferred. 
 
For designing 3-D fields, CTV, PTV, and OARs will be the same as those specified 
in the IMRT planning section (51).  CTV and PTV must be delineated.  Normal 
tissue dose constraints will also be the same.  We recommend the following field 
borders for 3-D fields: 
 
AP-PA field 
Superior: L5-S1 interspace 
Inferior: Ischial tuberosity 
Lateral: 1-cm exterior to pelvic brim 
 
Lateral field 
Superior: L5-S1 interspace 
Inferior: match to AP-PA fields 
Anterior: Pubic symphysis; bowel may be excluded as long as there is a 1.5 cm 
margin around the PTV to ensure adequate coverage of this volume 
Posterior: follow posterior curve of the sacrum to ensure complete coverage of the 
presacral space 
 
Boost volumes 
A 2-cm margin should be placed circumferentially on the primary GTV, involved 
nodal GTV, and presacral CTV to create the boost PTV.  The field arrangement used 
to treat this target may be at the discretion of the treating radiation oncologist. 


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7.3.4 Treatment Break Outline 
Pursuant with RTOG 0822: “Treatment interruptions are discouraged; however, they 
may be necessitated by uncontrolled diarrhea or other acute complications. The 
reason for and length of any such interruption must be documented. If the sum total 
of such interruptions exceeds 5 normally scheduled treatment days, this would 
constitute a major treatment violation. A minimum of 4 daily radiation therapy 
treatments are required in any given week. Any missed radiation treatments will be 
made up at the end of the treatment schedule, such that the total number of delivered 
1.8 Gy fractions remains 28. If chemotherapy is held, radiation therapy will 
continue.” 
 
Toxicity 
XRT Dose 
Grade 2 thrombocytopenia 
Continue at current dose. 
Grade 3 thrombocytopenia 
Hold until recovery to grade ≤1, then 
resume. 
 
Grade 4 thrombocytopenia 
Hold until recovery to grade ≤1 (platelets 
≥ 75 x109/L), then resume. 
Grade 3 neutropenia  
 
Hold until recovery to grade ≤1 , then 
resume. 
Grade 4 neutropenia 
 
Hold until recovery to grade ≤1, then 
resume. 
 
Grade ≥3 febrile neutropenia 
Hold until resolution of fever and 
neutropenia to grade ≤ 1. Hold until the 
ANC ≥ 1,500/mm3 and fever has 
resolved. Then resume treatment. 
 
References: 
RTOG 0822 Protocol, Section 6 (Radiation Therapy) 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?action=openFile
&FileID=4663 


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7.3.5 Capecitabine (Xeloda) 
Capecitabine shall be delivered at 825mg/m2 BID during IMRT radiotherapy. Dose 
modification shall occur as follows: 
 If ANC < 1000/mm3 capecitabine will be held until the blood counts recover 
above these values and the patient can resume full dosing 
 If platelet count < 100,000/mm3, capecitabine will be held until the blood counts 
recover above these values and the patient can resume full dosing 
 
Event Name 
Hand-Foot Skin Reaction 
Grade of Event 
Management/Next Dose for Capecitabine 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1. 
For the first appearance resume at 100% of the dose. 
For the second appearance, dose reduce to 650 mg/m2 
For the third appearance, dose reduce to 500 mg/m2 
For the fourth appearance, discontinue. 
Grade 3 
Hold until ≤ Grade 1.  
For the first appearance, dose reduce to 650 mg/m2 
For the second appearance, dose reduce to 500 mg/m2 
For the third appearance, discontinue. 
Grade 4 
Hold until ≤ Grade 1. 
For  the first appearance, dose reduce to 500 mg/m2 
For the second appearance, discontinue. 
 
Event Name 
Diarrhea 
Grade of Event 
Management/Next Dose for Capecitabine 
≤ Grade 1 
No change in dose 
Grade 2 
For the first appearance, dose reduce to 650 mg/m2 
For the second appearance, dose reduce to 500 mg/m2 
For the third appearance, discontinue.1 
Grade 3 
For the first appearance, dose reduce to 650 mg/m2 
For the second appearance, dose reduce to 500 mg/m2 
For the third appearance, discontinue.1 
1Capecitabine may be discontinued at the discretion of the investigator 
 


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7.4 
Surgery 
7.4.1 Patient Assessment 
After the patient has been identified as a candidate for the trial, the surgeon will 
assess the patient and will determine: 
1. 
Exact height and location of tumor with regards to the anal margin as 
measured by a rigid or flexible proctoscope and/or digital exam. 
2. 
Mobility of tumor as assessed if possible by rectal exam 
3. 
Type of surgical procedure: Abdomino-perineal resection vs. sphincter 
saving procedures, which will include colo-anal with mucosectomy vs. 
stapled anastomosis. 
7.4.2  Patient Preparation 
Routine pre-operative assessment will be undertaken as standard care.  Efforts will be 
made for the patient to be seen by a stomatherapist pre-operatively in order to mark 
the future site of either temporary ileostomy or permanent colostomy.  Bowel 
preparation, perioperative antibiotics, and venothromboembolic prophylaxis will be 
encouraged and administered at the discretion of the treating facilities.  Skin 
preparation, glucose monitoring, and temperature regulation will be at the discretion 
of the treating surgeon and facility.  
7.4.3 Tumor Assessment 
The following items will be assessed at the time of surgery either before the 
procedure begins or once the specimen has been removed.  
1. Macroscopic response to brachytherapy (complete vs. partial vs. non 
response)  
2. Height between tumor bed and anal margin, to assess feasibility of either 
colo-anal anastomosis vs. stapled anastomosis vs. abdomino-perineal 
resection (APR). 
3. Location of the tumor on the bowel wall (anterior/posterior). 
 
The pathologist should be orientated to the position of the tumor and should open the  
lumen of the specimen so that the response can be directly observed. We follow the 
criteria outlined by Mandard et al. with tumor regression grade (TRG) 1-2 
demonstrating a good response to therapy (52). 
7.4.4 Surgical Technique 
Surgery should occur between 8 and 12 weeks from the completion of neoadjuvant 
therapy.  
 
Patients will be positioned in lithotomy. The use of ureteral stents will be at the 
discretion of the treating surgeon.  Open and minimally invasive techniques are 
allowed. If preservation of the anal sphincter muscles is planned, a standard 
laparotomy will be undertaken. An assessment of the liver, peritoneum, pelvic organs 
(uterus/ovaries) should be performed.  The objective of the operation is a curative 


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procedure with full total mesentery excision (TME) of the rectum.   It will be 
expected that all attempts to perform a high ligation of the IMA will occur and that 
the nodes within this portion of the mesentery will be carefully examined.  The plane 
between the fascia propria of the rectum and the presacral fascia will be entered in 
the midline posteriorly.  Every attempt will be made to identify the hypogastric 
nerves along the pelvic side wall and the findings will be recorded as injured or 
preserved (See Appendix VI). It is expected that all tumors located in the mid and 
lower rectum will be removed with a complete TME.  All attempts will be made to 
achieve at least a 3-cm margin on the mesorectum and a 1-cm mucosal margin.  If the 
margin is in question, additional margin should be taken.  A frozen section may be 
performed at the discretion of the treating surgeon.  The surgeon will record their 
assessment of the TME as either complete, nearly complete, or incomplete recording 
difficulty encountered.  It will be at the discretion of the surgeon to perform either a 
straight end-to-end or side-to-end anastomosis with or without a colonic pouch or 
coloplasty.  Evaluation of the anastomosis will be performed from the abdominal 
side, i.e., tension-free anastomosis and from the perineal side, i.e., complete ring of 
the anastomosis and negative air test. All patients undergoing a resection with re-
anastomosis will have a diverting loop ileostomy performed.  If an APR is 
performed, the perineum will be removed in an oncological fashion with preservation 
of the radial margin either at the start of the procedure of at the end of the procedure.  
The perineum will be closed in a method which is at the discretion of the treating 
surgeon and the patient will be given a permanent stoma.   
 
Abdominal or perineal drainage will be left to the discretion of the surgeon. 
7.4.5 Post-Operative Assessment 
Standard post-operative care will be undertaken.  Length of stay, transfusion 
requirements, surgical site infections (including clinical and sub-clinical anastomotic 
leaks), and venothrombolic events as captured by the National Safety Quality 
Improvement Project (NSQIP) will be recorded. Any hospital mortality with cause of 
death will be recorded.  Any other intraoperative findings such as perineal wound 
infection (for patients undergoing APR), anastamotic leak (managed with IR 
drainage vs. requiring return to OR), or intraabdominal abscesses will be recorded. 
7.4.6 Follow-Up Evaluation 
Patient will be considered for stoma closure 2 to 3 months after surgery or following 
additional chemotherapy.  Prior to stoma closure, patient will have anastomosis 
evaluation by either standard contrast radiography direct in the rectum and or by 
rectal exam with sigmoidoscopy.  Any abnormal finding will be recorded and may 
delay stoma closure. 
7.4.7 Postoperative Adjuvant Chemotherapy 
Per standard of care and at the discretion of the treating physician, approximately 6-
10 weeks after surgery, patients will receive modified FOLFOX6 adjuvantly after 
resection for 6 months (12 cycles). Below is a recommended regimen but final plan is 
at the discretion of treating physician. 


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FOLFOX6:  
 
Day 1                                                            
 
Oxa infusion (2h)  
                          FA infusion (2h) 
 
                               5-FU bolus 
 
                                
 
 
FA 
                                   │ 5-FU CI  
 
OXA 
                        
                                      2h 
                                                            48h 
Day 1: 
Oxaliplatin: 85 mg/m² in 500ml glucose 5% solution, 2-h infusion 
 
Folinic acid (FA) 400mg/m² in 250ml glucose 5% solution, 2-h infusion 
simultaneously with the oxaliplatin infusion 
5-Fluorouracil (5-FU) bolus 400mg/m² following the oxaliplatin/FA infusions 
5-FU continuous infusion 2400 mg/m², 46-h infusion following the 5-FU bolus 
 
Cycle length: 14 days (2 weeks) 
 
Duration of treatment: 12 cycles  
7.5 
Follow-Up Assessments 
Patients will be followed per standard of care. For study purposes. an initial follow-up 
will occur post-operatively and then annually by PI and/or study team members. Every 
effort made to collect any SAE’s or hospitilizations that occurred in the year prior. QOL 
will in collected per the study calender   In the event this cannot be completed in person 
or online, it will be mailed out. 
7.5 
Supportive Care 
The following supportive care is recommended. However, it is ultimately at the discretion 
of the treating physician. 
7.5.1 Patients receiving Endo-HDR 
Proctitis and rectal pain are the main side effects reported among patients receiving 
Endo-HDR.  These symptoms are currently managed as follows: 
 Cortifoam enema (all patients) 
 Naproxen 375 – 500 mg (all patients; twice daily; discontinue 3 weeks before 
surgery) 
 Acetaminophen with codeine 300/30 mg (patients experiencing mild to moderate 
pain; take 3 – 4 times daily as needed) 
 Hydromorphone 2 mg  (patients with severe pain only; take 3 – 4 times per day 
as needed) 
 
 


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7.5.2 Patients receiving External Beam Radiotherapy 
Diarrhea, skin irritation, fatigue, urinary tract irritation, and decreased blood counts 
are the main side effects experienced during concurrent chemotherapy and pelvic 
radiation therapy.  Standard supportive care measures may be used at the treating 
physician’s discretion throughout the course of therapy, including antidiarrheal 
agents (loperamide, etc.), skin creams, and phenazopyridine (Pyridium).  Specific 
guidelines for dose-reducing capecitabine as needed are given in Section 7.3.5.   
7.6 
Subject Withdrawal/Removal 
Patients will be removed from the study for the following reasons: 
 
Unacceptable toxicity from therapy. Toxicity must be appropriately 
documented. 
 
Development of intercurrent, non-cancer related illness that prevents 
either continuation of therapy or regular follow-up 
 
The patient decides to discontinue enrollment in the protocol at any time 
and for any reason 
 
Continuation of participation could be harmful 
 
Pregnancy 
 
The patient needs treatment not allowed in the study 
 
All reasons for discontinuation of treatment must be documented. 
 
 Patients who prematurely discontinue radiation treatment but undergo surgical 
exploration will be followed per the prescribed protocol schedule.  
 Patients who prematurely discontinue radiation treatment and do not undergo 
surgical exploration will be followed for survival for five years. 
 Patients who complete radiation treatment and do not undergo surgical 
exploration will be followed for survival for five years. 
7.7 
Costs 
Patients and/or their insurance companies will be responsible for the cost of all 
procedures and treatments under this protocol. 


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8. COORDINATING CENTER 
8.1 
Responsibilities 
Johns Hopkins Hospital will serve as the coordinating center for this study.   
Coordinating Center functions will include: 
1. 
Coordination of all data collection and analyses 
2. 
On site monitoring/auditing of patient study charts and source documents 
at regular intervals that will be dictated by the rate of enrollment and 
treatment 
3. 
Coordinating among the sites and reporting to a data monitoring 
committee.  Each site will be expected to provide information on adverse 
events to their IRB as per each institution’s procedures. 
 
A complete discussion of the roles and responsibilities of the Coordinating Center and 
Participating Sites can be found in Appendix II. 


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9. STUDY CALENDAR 
 
Evaluation 
Baseline1 
RADIATION TREATMENT7 
Pre-Op8 
SURGERY9 
Post-Op10 
CHEMOTHERAPY12 
Post Surgical Follow-Up13 
1Y 
2 Y 
3Y 
4Y 
5Y 
Informed Consent 
X 
  
  
  
 
  
 
  
 
H&P 
X 
X 
X 
X 
 X 
X 
X  
X 
Performance Status 
X 
X 
X 
X 
 X 
X 
X  
X 
Pregnancy Test2 
X 
 
 
 
 
 
 
 
Concomitant Medications3 
X 
 
 
X 
X 
X 
X 
X 
Endoscopic Ultrasound4 
X 
 
 
 
  
 
  
 
Marker Placement5 
X 
 
  
 
  
 
  
 
Research Biopsy5 
(optional) 
X 
 
  
 
  
 
  
 
FDG-PET/CT 
X 
X 
  
 
  
 
  
 
Pelvic MRI 
X 
X 
  
 
  
 
  
 
CT C/A/P 
 
 
  
X 
X  
X 
 X 
X 
CBC w/ Diff, CMP 
X 
X 
X 
X 
X 
X 
X 
X 
CEA 
X 
X 
X 
X 
X 
X 
X 
X 
Testosterone6 
X 
X 
 
X 
X 
X 
X 
X 
Biomarkers (optional, lead 
site only) 
X 
X 
X 
X 
X 
X 
X 
X 
TME Evaluation 
 
 
X11 
 
 
 
 
 
Toxicity Evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
QOL Surveys14 
X 
X 
X 
X 
X 
X 
X 
X 
1 Must be conducted within 6 weeks of RT initiation 
2 Required for premenopausal women who have not been surgically sterilized within 1 month of RT initiation. All women of child-bearing 
potential must have negative pregnancy test (urine or serum). 
3Specifically: phosphodiesterase inhibitors, bi- and tri-mix injections, testosterone therapy, vaginal estrogen cream, and hormone replacement 
therapy 
4 Must be conducted within 3 months of RT initiation 
5 Must be conducted within 3 weeks of RT initiation; biopsy should include tumor and normal tissue sample (see Section 10.4.4) 
6 Total and free testosterone level for male participants only 
7 Patients will be monitored for toxicity weekly during RT 
8 Within 4-8 weeks pre-surgery 
9 Patients will undergo surgery 8-12 weeks from RT completion 
10 Within 4-12 weeks post-surgery 
11 Documentation must be complete within 1 week post-surgery 
12 Adjuvant chemotherapy is standard and will not be monitored/tracked by the Principal Investigator or the study team 
13 Annual follow-up appointments will be based on the date of surgery and have a tolerance window of +/- 30 days 
14 See 9.1 for quality of life survey calendar 
 


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9.1 
Quality of Life Survey Calendar 
 
Measure 
Baseline 
Pre-op 
Post-Op 
Post-Surgical Follow-Up 
Y1 
Y2 
Y3 
Y4 
Y5 
Marital/Partnered Status 
X 
X 
X 
X 
X 
X 
Sexual Relationship Screener/ Sexual 
Activity Items 
X 
X 
X 
X 
X 
X 
X 
X 
EORTC QLQ C30 
X 
X 
X 
X 
X 
X 
X 
X 
EORTC CR38 
X 
X 
X 
X 
X 
X 
X 
X 
CRF 21 
X 
X 
X 
X 
X 
X 
X 
X 
FSFI/IIEF 
X 
X 
X 
X 
X 
X 
X 
X 
Sexual Aids for Women/Men 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment-Related Stress Items 
X 
X 
Perceived Stress Scale 
X 
X 
X 


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10. MEASUREMENT OF EFFECT 
10.1 Central Imaging Review and Determining Response 
Initial imaging including rectal protocol MRI and FDG-PET/CT scan will be performed 
within 6 weeks of initiating RT.  At 4-8 weeks following RT repeat MR imaging with 
DWI and CE-MR and FDG-PET/CT will be performed. Scans will be assessed using 
criteria outlined in the Mercury study. PERCIST and RECIST will be centrally 
determined on PET/CT and MRI images as outlined in Appendix VII at the completion of 
the study. We will integrate FDG-PET/CT into Endo-HDR treatment planning to improve 
our ability to accurately delineate tumor boundaries. We will co-register FDG-PET 
images with the MRI planning scan using the CT component of the PET/CT. To control 
for the effects of PET window/level, we will contour the tumor boundary at a threshold of 
40% of the maximum SUV value as validated in previous studies. We have previously 
shown that FDG-PET/CT is an important investigative tool in the initial evaluation of 
primary rectal cancer and that it can accurately predict response to NCRT (53).  Our 
initial data demonstrated that PET/CT is more accurate at initial staging of rectal cancer 
than conventional CT imaging.  More recently, we have shown that FDG-PET/CT is an 
effective method of monitoring the response of tumors to NCRT (54).  Serial FDG-
PET/CT scans demonstrated that changes in the visual response score (VRS) and SUV 
were able to predict tumor downstaging on final pathology. To better evaluate tumor 
response, a newer method to examine the relation between dose and response as 
measured by 18F-FDG uptake in 192Ir HDR brachytherapy and IMRT treated rectal cancer 
will be utilized at the voxel level as well as for the whole tumor. Furthermore, newer 
modalities in MR may provide additional information to assess tumor response.  
Specifically, functional MR imaging can essentially provide in vivo physiologic and 
metabolic information via spectroscopy, diffusion, and perfusion techniques (55). 
Functional MRI has been evaluated at our institution in the management of metastatic 
colorectal disease to the liver (56). Data regarding the use of functional MRI in the 
assessment of response in adenocarcinoma of the rectum is limited; however, the ability 
to perform physiologic evaluation of tumors may help predict for pCR following Endo-
HDR and IMRT.   
10.2 Pathologic Evaluation of Total Mesorectal Specimen 
10.2.1 Gross Specimen 
Pathology report shall include the T and N staging according to the 2002 AJCC 6th 
Addition Guidelines as well as histologic type, depth of invasion, tumor grade, 
presence of lymph-vascular or perineural invasion and the surgical margin status.  
Resection margin shall be designated as R0, no residual disease; R1, microscopic 
residual disease or R2, gross residual disease.   
 Pathologic stage evaluation using the TNM staging system of the 
AJCC/UICC 
 Uniform reporting of all additional stage-independent, prognostically 
significant histological parameters 
 Pathologic evaluation of the specimen  


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10.2.2 Macroscopic Examination 
The completeness of the mesorectum is scored as follows: 
 
 Incomplete (#1) 
Little bulk to the mesorectum.  Defects in the mesorectum down to the 
muscularis propria. (After transverse sectioning [see below] – very irregular 
circumferential margin) 
 Nearly Complete (#2) 
Moderate bulk to the mesorectum. Irregularity of the mesorectal surface with 
defects greater than 5mm but none extending to the muscularis propria. No 
areas of visibility of the muscularis propria except at the insertion site of the 
levator ani muscles. 
 Complete (#3) 
Intact bulky mesorectum with a smooth surface. Only minor irregularities of 
the mesorectal surface. No surface defects greater than 5 mm in depth. No 
coning towards the distal margin of the specimen. (After transverse 
sectioning– smooth circumferential margin) 
10.3 Quality of Life Toxicity Comparison 
10.3.1 EORTC 
The current literature regarding health-related QOL for rectal cancer patients treated 
with pelvic radiotherapy is sparse and suffers from several limitations, including 
retrospective, cross-sectional study designs, use of QOL instruments that have not 
been validated, and a lack of emphasis on the effects of non-surgical treatment 
modalities on QOL. In order to help bridge this gap, we have recently completed a 
phase II multi-institutional (University of Michigan and Johns Hopkins Hospital) 
study evaluating QOL in patients receiving conventional neoadjuvant 5-FU based 
CRT as measured by the EORTC QLQ-C30, QLQ-CR38 and CR29 instruments (59, 
60). The frequency and severity of disease- and treatment-related symptoms before, 
during, and following CRT were obtained. Eligible patients included rectal cancer 
patients who received NCRT (45-54 Gy) using a standard 3-field technique. The 
results of this study (N=50) were presented at the ASCO/ASTRO GI 2011 meeting 
and the manuscript was recently published (Herman et al. 2013).  During NCRT, 
patients had a statistically and clinically significant decline in global QOL, which 
normalized following completion of NCRT. During NCRT, patients also experienced 
a significant increase in GI symptoms (21 to 27, p=0.028), urinary symptoms (16 to 
30, p < 0.0001), male sexual dysfunction (23 to 34, p=0.013), and chemotherapy 
related side effects (8 to 20, p = 0.0001). Interestingly, while these measures returned 
to baseline 1 month post-CRT, overall sexual function and sexual enjoyment 
remained persistently low after treatment end compared to pretreatment levels. Those 
patients who experienced grade 3 toxicity during treatment showed markedly 
decreased global QOL. 
Given its potential to improve the side effect profile of radiation delivery for rectal 
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through prospective (pre/post) short and long term (5 years) QOL assessment with 
validated questionnaires.  The EORTC QLQ-CR38 is an internationally validated, 
colorectal cancer-specific quality of life index, and the EORTC QLQ-30 is an 
internationally validated questionnaire assessing general quality of life.  Patients will 
be asked to complete both of these assessments.  
10.3.2 Stress Evaluation 
Cancer treatments can cause significant stress for cancer patients (61) because they 
lead to physical and psychological side effects and disruptions in daily life and social 
activities. Stress levels tend to differ according to the stage in treatment for cancer 
patients, with the highest levels occurring around diagnosis and treatment, and often 
declining over time (62). Presumably, cancer treatments could have differing effects 
on patients’ stress levels and impact in their daily life depending on the severity of 
side effects and their length of course. Comparisons between Endo-HDR, the newer 
radiation therapy under examination in the current trial, and 5-FU (Cap) + RT on their 
impact on patients’ stress levels have not been conducted. By limiting the dose and 
length of treatment, it is hypothesized that Endo-HDR may be perceived as less 
stressful and having less of a negative impact on daily life compared with 5-FU (Cap) 
+ RT. To compare the trajectory of patient stress in the two treatment conditions, 
study patients will complete 7 items assessing impact on daily life, which were 
developed for this study or assessed previously in colorectal cancer studies (63), and 
the Perceived Stress Scale (64), a widely used 10-item scale that measures global life 
stress over the past month. 
10.3.3 Sexual Function 
Increasing research finds that long-term sexual function is impacted by radiation 
therapy for rectal cancer patients (65, 66). In a prior research study by our team (67), 
we examined changes in patient-reported QOL during and after neoadjuvant 
chemoradiation in 50 patients with locally advanced rectal cancer to establish a 
baseline for future research. Findings revealed that at 1 post-CRT, most physical 
symptoms returned to pre-CRT levels, but sexual enjoyment and sexual function 
remained persistently diminished. While suggestive, our ability to demonstrate a 
potential impact on sexual outcomes would be strengthened by the use of 
comprehensive validated questionnaires specifically designed to measure multiple 
dimensions of sexual function. Given the reduced spread to nearby organs, we 
hypothesize that the impact of newer radiotherapy techniques on sexual function will 
be reduced when compared to older techniques with greater spread. In order to test 
this hypothesis, patients will complete gold-standard, comprehensive sexual function 
measures (68, 69), the Female Sexual Function Index (70) and the International Index 
of Erectile Function (71) at all study time points. In addition, because use of 
therapeutic aids (e.g., phosphodieterase inhibitors such as Viagra, vaginal lubricants) 
can impact self-reported sexual function, we will assess patients’ use of therapeutic 
aids through 8 items assessing use of such aids over the past month (4 for women; 4 
for men). These items are selected from the Therapeutic Aids domain of the PROMIS 
Sexual Function and Satisfaction measure, which has been extensively validated in 
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The complete texts of these assessments are listed in Appendix VI.  It is hypothesized 
that Endo-HDR will limit the dose to sexual organs as well as the anal sphincter in 
patients who do not have direct sphincter invasion with tumor. By doing so, Endo-
HDR may result in long term preservation of sexual and anorectal function resulting 
in an improved toxicity profile and QOL.  
10.4 Molecular Biology Correlative Studies 
10.4.1 DNA Damage Response 
With regard to biomarkers, we will compare how Endo-HDR versus NCRT affects 
DNA damage response pathway and correlate with pathologic complete response.  
We will determine whether particular mutations predict for pCR rates (VEGF/EFGR) 
and evaluate whether circulating tumor DNA levels and DNA damage response 
pathways predict for pCR following Endo-HDR.  Immunohistochemical detection of 
activated DNA damage signaling in human tumors will be evaluated on pre-treatment 
tumor biopsies and correlated with pCR rates following Endo-HDR. 
10.4.2 VEGF-/EGFR+ Status, Hypoxia Markers 
Dr. Vuong’s group found that tumors with VEGF-/EGFR+ status were more likely to 
respond to Endo-HDR (pCR). This is contrary to what has been reported in patients 
receiving standard neoadjuvant CRT. Furthermore, we will prospectively evaluate 
whether circulating levels of tumor DNA correlate with staging (lymph node status), 
pCR rates, and other outcomes (survival, patterns of recurrence).  In addition to 
VEGF and EGFR, other well-described genetic alterations (p53, BRAF, KRAS, 
PIK3CA, γ-H2AX, and XRCC1) and hypoxia related markers will be evaluated and 
may predict for response to Endo-HDR versus IMRT following FOLFOX 
chemotherapy. 
10.4.3 Microbial Associations of Rectal Cancer 
We will collect a tumor and normal tissue biopsy sample at the time of initial 
sigmoidoscopy. The sample will be snap frozen and later analyzed using microbial 
sequencing techniques to define the microbial associations of rectal cancer. The 
results will be analyzed in conjunction with microbial studies of colon cancer already 
underway.  
10.4.4 Cancer Genome Sequencing to Determine Genetic Predictors of Response to Endo-
HDR and IMRT 
Whole cancer exome analysis will be performed on a subset of cases of strong 
responders and non-responders in an unbiased manner.  Twenty thousand genes will 
be interrogated using tumor samples and whole blood using the Agilent capture 
platform and the Illumina HiSeq2000.  Samples will be sequenced at a depth of 100-
200X and analysis of these results will take into account clinical response.  
Correlation with clinical and pathologic response to therapy, disease free survival 
and overall survival will be performed against all the somatic genetic alterations 
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10.4.5 Specimen Processing, Storage, and Shipping  
All participating institutions must ask patients for consent to participate in correlative 
science studies, although patient participation is optional.  
 
Blood samples for research purposes will be drawn prior to radiation treatment, pre-
operatively, post-operatively and at each follow-up along with the patient’s regular 
labs. For each collection, up to 8mL will be drawn. Immediately, after collection, 
blood will be centrifuged at 3000 RPM for 10 minutes and plasma collected. The 
supernatant will be aliquoted for storage at -80°C into 10 separate tubes. The pellet 
will also be stored in a separate tube at -80°C. 
 
Biopsy samples for research purposes will be divided in half. One half will be flash 
frozen with liquid nitrogen. The other half will be fixed into a paraffin embedded 
sample. 
 
All specimens must be labeled with the protocol number, site number, subject  
number, patient’s initials, collection date and type of specimen collected (e.g., serum, 
whole blood). For tissue specimens the labeling should include institutional surgical 
pathology case number and block number. 
 
All samples will be stored at participating institutions until completion of the trial. 
Batch shipments should be addressed to: 
 
Dr. Amol Narang 
Attn: Joyce Schanne 
401 N. Broadway 
Suite 1440 
Baltimore, MD 21231 
 (410) 502-3823 
 
Upon shipment, participating institutions must notify coordinating center Research 
Program Coordinator with delivery information. 
 
Please be sure to use a method of shipping that is secure and traceable. Extreme heat 
precautions should be taken when necessary. Samples should be shipped Monday-
Thursday by overnight service. DO NOT SHIP SPECIMENS ON FRIDAYS OR 
SATURDAYS. 
 
11. ADVERSE EVENT REPORTING 
11.1 General 
Adverse event collection and reporting is a routine part of every clinical trial. This study 
will use the descriptions and grading scales found in the NCI Common Terminology 
Criteria for Adverse Events version 4.0 (CTCAE v 4.0) that is available at 
http://ctep.cancer.gov/reporting//ctc.html.  


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Adverse events not listed in the NCI Common Terminology Criteria for Adverse Events 
will be evaluated using the following criteria: 
 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL 
 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self care ADL 
 
Grade 4: Life-threatening consequences; urgent intervention indicated 
 
Grade 5: Death related to AE 
 
Information on all adverse events, whether reported by the participant, directly observed, 
or detected by physical examination, laboratory test or other means, will be collected, 
recorded, followed and reported as described in the following sections.  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. The investigator should notify the IRB 
and any other applicable regulatory agency of any unanticipated death or adverse event 
occurring after a participant has discontinued or terminated study participation that may 
reasonably be related to the study.  
11.2 Definitions 
11.2.1 Adverse Event (AE) 
An adverse event is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition during or following an exposure to a 
treatment, whether or not considered causally related to the treatment. An undesirable 
medical condition may be symptoms (headache, nausea), signs (tachycardia, enlarged 
liver), or abnormal results of an investigation (MRI, laboratory finding). 
11.2.2 Serious adverse event (SAE) 
A serious adverse event is an undesirable sign, symptom, or medical condition 
which: 
 
Results in death. 
 
Is immediately life threatening. 
 
Requires 
in-patient 
hospitalization 
or 
prolongation 
of 
existing 
hospitalization 
 
Is a congenital abnormality or birth defect 
 
Unexpected event that cause harm or place person at a greater risk of 
harm than was previously known or recognized, and which was possibly 
related to the research. Unexpected means that the event was not 
described in the consent form or the event exceeded the expected severity. 
 
Is an important medical event that may jeopardize the patient or may 
require medical intervention to prevent one of the outcomes listed above. 


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Events not considered to be serious adverse events are hospitalizations for: 
 
routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
 
elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
 
emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 
 
respite care 
11.2.3 Expectedness  
 
Expected: Expected adverse events are those that have been previously 
identified as resulting from administration of the agent. For the purposes of this 
study, an adverse event is considered expected when it appears in the current 
adverse event list, the Investigator’s Brochure, the package insert or is included 
in the informed consent document as a potential risk. 
 
Unexpected: An adverse event is considered unexpected when it varies in 
nature, intensity or frequency from information provided in the current adverse 
event list, the Investigator’s Brochure, the package insert or when it is not 
included in the informed consent document as a potential risk 
11.2.4 Attribution  
Attribution is the relationship between an adverse event or serious adverse event and 
the study treatment. Attribution will be assigned as follows: 
 
Not Related: The adverse event is clearly related to other factors such as the 
subject’s clinical state, environmental factors, or other modes of therapy or 
concomitant drugs administered to the subject. 
 
Not likely: There is a temporal relationship to investigational product 
administration, but there is not a reasonable causal relationship between the 
investigational product and the AE.  
 
Possible: The adverse event follows a reasonable temporal sequence from 
administration of the study drug, and/or follows a known response pattern to 
the study drug, but could readily have been produced by the subject’s clinical 
state, environmental factors, or other modes of therapy or concomitant drugs 
administered to the subject. 
 
Probable: The adverse event follows a reasonable temporal sequence from 
administration of the study drug and follows a known response pattern to the 
study drug, and cannot readily have been produced by the subject’s clinical 
state, environmental factors, or other modes of therapy or concomitant drugs 
administered to the subject. 
 
Definite: There is a reasonable causal relationship between the investigational 
product and the AE. The event responds to withdrawal of investigational 
product (dechallenge), and recurs with rechallenge when clinically feasible. 


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11.3 Potential Adverse Events 
Signs and symptoms of disease progression are not considered AEs. The development of 
a new cancer should be regarded as an AE. New cancers are those that are not the 
primary reason for administration of study treatment and have been identified after 
inclusion of the patient into the clinical study. 
 
Because patients are receiving standard treatments, which are not part of this study, their 
treating physician will be counseling them on the risk of their treatments, including the 
risk of surgery, radiation therapy, and/or chemotherapy, whichever is appropriate for the 
type and the stage of their cancer.  
 
Phlebotomy can cause pain, bleeding, and rare needle site infection. PET imaging results 
in low dose radiation exposure, which has an extremely small risk of causing a secondary 
cancer.  
11.4 Endoscopy & Marker Implantation 
The use of endoscopy to initially assess and follow-up rectal cancer following 
neoadjuvant treatment is routine.  For the purposes of this study it is necessary prior to 
therapy to place endoscopic markers to mark the tumor for guidance to place the 
endoluminal catheter.  The risk of flexible sigmoidoscopy and marker placement are 
minimal and include bleeding in less than 1 in 100 patients and perforation in less than 1 
in 1,000 patients.  Generally, this procedure is done without sedation but sedation will be 
provided if the patient requests the use of it.  The risks of sedation include heart 
arrhythmias, hypotension, respiratory distress, and confusion.  All endoscopic procedures 
are performed in a monitored setting with a nurse to minimize this risk.  
11.5 Endorectal Brachytherapy Radiation Therapy 
 Rectal bleeding:  The risk of minimal bleeding after catheter placement is common 
and nearly all patients will have bleeding from their tumor.  The risk of major 
bleeding from this procedure is similar to endoscopic evaluation and is <1%. 
 Rectal perforation:  This risk of perforation from insertion of the endoluminal probe 
is less than 1% and is similar to endoscopic procedure.  The catheter is placed using 
direct image guidance. 
 Rectal discomfort:  Rectal discomfort from the application of the brachy probe will be 
common to all patients.  To minimize the risk of this, routine endoscopic assessment 
of rectal luminal size prior to port placement will be performed and local anesthetic 
gel will be used if necessary.                                                                   
 Poor catheter placement with inadequate treatment dose administration:  All patients 
prior to treatment will have endoscopic radiopaque markers placed to outline the 
tumor to guide in catheter placement.  All patients prior to HDRBT treatment will 
undergo simulation planning to assure full tumor treatment.  The catheter is guided 
intraluminally using real time imaging (C-arm CT scan). 
 


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Toxicity for HDRBT is reportedly limited to grade 1-2 proctitis with less than 1% of 
patients experiencing a grade three toxicity.  Rare systemic side effects of radiation have 
occurred and are listed below. 
 
Expected Adverse Events from HDRBT 
More Frequent (>10%) 
Less Frequent (< 5%) 
Dermatologic/Skin 
 Rash 
 Radiation Dermatitis 
 Puritis/Itching 
 Dry Skin 
Gastrointestinal 
 Proctitis 
 Diarrhea 
 Rectal Pain 
 Rectal Bleeding 
Renal 
 Urinary Frequency 
Dermatologic/Skin 
 Moist Desquamation 
Gastrointestinal 
 Ulcer 
 Obstruction (small bowel NOS) 
Secondary Malignancy 
Renal 
 Renal Failure 
Blood/Bone Marrow 
 Anemia 
 Pancytopenia 
Since we are just learning about treating cancers of the distal bowel with this type of 
radiation, there may also be side effects and discomforts that are not yet known. 
11.6 Intensity Modulated Radiation Therapy 
All radiation related adverse events will be recorded on the local toxicity case report 
forms.  Neoadjvuant intensity modulated radiation therapy (IMRT) and capecitabine 
chemotherapy is considered standard of care treatment for localized rectal cancer.  
 
In accordance RTOG 0822, “side effects expected from radiation therapy include fatigue, 
rectal frequency, diarrhea, urinary frequency, dysuria, loss of pubic hair, 
hyperpigmentation of the skin in the treatment field, lower blood counts. Rare but 
possible side effects include small bowel obstruction, fistula, small bowel ulceration, wet 
desquamation, infection, and urethral obstruction.” 
 
The following are common potential short term reactions/ risks that are associated with  
external beam radiation therapy: 
Increased urinary frequency, urgency, pain, mild to moderate increase in frequency and  
looseness of bowel movements, fatigue, diarrhea, decreased blood cell count, temporary  
hair loss in area treated, skin redness and irritation in area treated, vaginal inflammation 
and bladder inflammation. 
 
The following are uncommon potential short term reactions/ risks associated with 
external beam radiation therapy: 
Nausea or vomiting, darkened skin and dryness in area treated, blood in the urine or 
stool, nausea or vomiting, painful bowel movements, hemorrhoidal bleeding, increased 
flatulence (gas), urine or stool leakage, severe difficulty with urination or bowel 
movements requiring a treatment break, such as for an obstruction requiring surgery. 


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The following are common potential long term reactions/ risks associated with external 
beam radiation therapy: 
Increased tendency to develop flatulence or diarrhea, more frequent urination and the 
urine cannot be held as long as normal, impotence or sterility/infertility, temporary 
bleeding in the gastrointestinal tract or genitourinary tract (bladder, prostate, urethra), 
subsequent surgery in the treated area may be more difficult, early menopause/sterility, 
and decreased vaginal secretions. 
 
The following are uncommon long term reactions/ risks associated with external beam 
radiation therapy: 
Occasional small amount of bleeding from the bladder or rectum, chronic diarrhea, 
urinary frequency, narrowing of the vaginal cavity, severe scarring in the vagina 
resulting in pain during intercourse, rectal stricture, urethral stricture (narrowing of the 
urinary channel that could require surgery), discomfort in the prostate area or perineum,  
leakage of urine or stool, injury to organs which may require major surgery, such as 
removal or the bladder or bowel, and swelling of the legs or genitalia. 
 
The following are rare potential long term reactions/ risks associated with external beam 
radiation therapy: 
Injury to the hips or bones which may require surgery, bowel complications requiring 
surgical procedure, urinary complications requiring surgical procedure, osteopenia, and 
femoral head fracture. 
 
The following is an extremely rare potential reaction/ risk associated with external beam  
radiation therapy: 
Tumors caused by radiation. 
 
References: 
RTOG 0822 Protocol, Section 6 (Radiation Therapy) 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?action=openFile&Fi
leID=4663 


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11.7 Surgery 
All patients in this study will have a temporary ileostomy (diversion of the bowel into a 
bag) at the time of surgery unless they are having an APR, in which case they will have a 
permanent colostomy. This is done to decrease the risk of a leak or complication 
following surgery. In most cases this ileostomy is temporary, however, depending on the 
location of the tumor, it may be permanent. 
 
Expected Adverse Events for Surgery 
More Frequent (>10%) 
Less Frequent (<1%) 
 Infection of wound 
 Intra-abdominal abscess 
 Urinary retention 
 Urinary tract infection 
 Ileus 
 Stoma irritation 
 Pain/Rectum 
 Anastomotic suture separation/leak 
– 10% in HDRBT literature 
 Dehydration 
 Thrombosis/Embolism 
 Pneumonia 
 Cardiac Ischemia/Infarction 
 Fistula – 
rectovaginal/rectourethral/perineal 
 Fecal incontinence 
 Stricture at suture line 
11.8 Chemotherapy 
Chemotherapy is considered standard of care.  Only grade 3 or greater side effects 
thought to be related to chemotherapy will be recorded. Since this is standard of care 
treatment, adjustments made to the chemotherapy regimen are left to the discretion of the 
treating oncologists. 
 
The following are very common potential side effects of capecitabine (occurring in more 
than 50 out of 100 people): 
Anemia hand-and-foot syndrome. 
 
The following are common potential side effects of capecitabine (occurring in 20 to 50 
people out of 100): 
Fatigue or weakness, vomiting, abdominal pain, loss of appetite, neutropenia, risk of 
infection, mouth sores, unusual burning or tingling sensations in hands or feet. 
 
The following are less common potential side effects associated with capecitabine 
(Occurring in 5 to 20 people out of 100): 
Constipation, eye irritation, vision changes, or conjunctivitis, difficulty breathing, pain 
(including back pain, muscle pain, or joint pain), lethargy, headaches, indigestion or 
heartburn, dizziness, insomnia dehydration, coughing, hair loss, taste changes and mood 
changes. 
 


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The following are even less common potential side effects of capecitabine (occurring in 
less than 5 people out of 100): 
Nosebleeds, sore throat, stomach ulcers, nail problems, increased sweating, sensitivity to 
the sun, hot flashes, drowsiness, shakiness, weight gain, weight loss, high triglycerides, 
coughing, asthma, pneumonia, hypotension, hypertension, and vertigo. 
 
Serious side effects we will be looking for very closely will be: 
Depression, signs of blood clots, blood in the stool, very severe constipation, nausea, 
vomiting, or mouth sores, severe redness of the hands or feet, an increase in tumor size or 
appearance of new tumors, a fever or signs of infection, signs of liver problems and signs 
of allergic reaction.  
11.9  Risks of Blood Draws 
About 8ml (1 ½ teaspoons) of blood may be drawn before radiation, after radiation, 
before surgery, and during follow-up for research purposes. Whenever possible, these 
samples will be obtained at the same time as other routine laboratory studies.  Although 
trained phlebotomists will be obtaining the blood samples, there are minimal risks 
associated with this procedure.  Taking blood may cause some discomfort, bleeding, or 
bruising where the needle enters the body, and there is a small risk of infection.  In rare 
cases, blood drawing may result in fainting.   
11.10 Risks of Radiographic Imaging 
Imaging studies (MRI, FDG-PET/CT) are part of standard clinical care. Patients will be 
given a clinical consent form for each imaging procedure that explains the risks of the 
procedures. 
11.11  Risks of completing the study questionnaires 
Patients may get tired or bored when they answering questions or completing 
questionnaires.  
11.12 Reporting Procedures 
11.12.1General 
Adverse events will be recorded at each visit. If an adverse event requiring medical 
attention occurs between visits, this will be recorded as well. The variables to be 
recorded for each adverse event include, but are not limited to, onset, resolution, 
intensity, action taken, outcome, causality rating and whether or not it constitutes an 
SAE. The intensity of the adverse event should be captured using CTCAE criteria, 
version 4.0, when possible.  
 
Pregnancy should be excluded before enrollment. Pregnancy in itself is not reported 
as an AE unless there is a suspicion that an investigational product may have 
interfered with the effectiveness of a contraceptive medication.  
 
All adverse events will be captured on the appropriate study-specific case report 
forms (CRFs).  


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11.12.2 
Institutional Review Board 
All adverse events and serious adverse events will be reported to the IRB per current 
institutional standards. If an adverse event requires modification of the informed 
consent, these modifications will be provided to the IRB with the report of the 
adverse event. If an adverse event requires modification to the study protocol, these 
modifications will be provided to the IRB as soon as is possible. 
11.12.3       SAE Guidelines for Johns Hopkins Hospital 
All SAEs, with the exception of death, must be reported to the Johns Hopkins 
Medicine Institutional Review Board (JHM-IRB) within 10 working days of the 
Principal Investigator learning of the event. Reporting for the death of a patient which 
was unexpected (i.e.: not related to a risk of participation that was listed in the 
protocol or the consent document, and was more likely than not to be caused by the 
research procedure/intervention) must be reported to the JHM-IRB within 3 working 
days of when the Principal Investigator receives the report of the death. Reporting for 
death of a participant that was expected due to the nature of the patient’s underlying 
disease or condition, or identified as caused by a possible risk of the study 
procedure/intervention as described in this protocol or consent form, must be reported 
to the JHM-IRB within 10 working days from the time the Principal Investigator 
learns of the event. If death occurs 30 days after the participant has stopped or 
completed their study treatment, the Principal Investigator does not have to report the 
death until the time of continuing review. 
 
12. DATA AND SAFETY MONITORING PLAN  
This is a DSMP Level I study under the SKCCC Monitoring Plan (see Appendix I). A Level I 
study requires both internal and external data monitoring. The Principal Investigator is 
responsible for internal monitoring for both safety and data quality. External data monitoring will 
be performed by the SKCCC at Johns Hopkins Clinical Research Office Quality Assurance 
Program (CRO QA).  
 
Data and safety monitoring oversight will be conducted by the SKCCC at Johns Hopkins Safety 
Monitoring Committee. Per the SKCCC at Johns Hopkins Safety Monitoring plan, the CRO QA 
will forward summaries of all monitoring reports to the Safety Monitoring Committee for 
review. All reportable anticipated and unanticipated protocol events/problems and amendments 
that are submitted to the IRB will also be reviewed by the Safety Monitoring Committee Chair 
(or designee) and QA manager. 
12.1 Data Recording 
Data will be collected on Case Report Forms (CRFs). These CRFs will be completed by 
the Study Coordinator. The CRFs for each subject will be kept in a separate research 
binder. Along with each completed CRF there will be corresponding source 
documentation filed for verification. The Principal Investigator, Research Study Nurse, 
and Study Coordinator will informally meet on a regular basis to make sure that the trial 
is progressing as mandated by the protocol. The CRO will audit this trial per their 


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standards to ensure and verify that the protocol is being carried out according to 
specifications as well as to verify that data included on subject CRFs are accurate. Exit 
reports generated as a result of these CRO audits will be forwarded to both the Safety 
Monitoring Committee as well as to the IRB of record for review. 
 
13. REGULATORY CONSIDERATIONS 
13.1 Protocol Review and Amendments 
Information regarding study conduct and progress will be reported to the Institutional 
Review Board (IRB) per the current institutional standards. 
 
Any changes to the protocol will be made in the form of an amendment and must be 
approved by the IRB prior to implementation.  
13.2 Informed Consent 
The investigator (or his/her designee) will explain to each subject the nature of the study, 
its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject will be informed that 
participation in the study is voluntary, that she may withdraw from the study at any time, 
and that withdrawal of consent will not affect her subsequent medical treatment or 
relationship with the treating physician(s) or institution. The informed consent will be 
given by means of a standard written statement, written in non-technical language, which 
will be IRB approved. The subject should read and consider the statement before signing 
and dating it, and will be given a copy of the document. No subject will enter the study or 
have study-specific procedures done before his/her informed consent has been obtained. 
 
In accordance with the Health Information Portability and Accountability Act (HIPAA), 
the written informed consent document (or a separate document to be given in 
conjunction with the consent document) will include a subject authorization to release 
medical information to the study sponsor and supporting agencies and/or allow these 
bodies, a regulatory authority, or Institutional Review Board access to subjects’ medical 
information that includes all hospital records relevant to the study, including subjects’ 
medical history. 
13.3 Ethics and GCP 
This study will be carried out in compliance with the protocol and Good Clinical 
Practice, as described in: 
 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations). 
3. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 
1964, amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 


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The investigator agrees to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of Good Clinical Practice that it conforms to.  
14. STATISTICAL CONSIDERATIONS 
14.1 Endpoints 
14.1.1 Study Design 
This is a multi-institutional, randomized, two-arm, phase II trial of endorectal 
brachytherapy alone (Endo-HDR) versus intensity modulated external beam 
radiotherapy  (IMRT) or 3-D conformal radiation therapy with capectitabine in 
patients with stage II/III rectal distal adenocarcinoma. Patients enrolled in the study 
will be randomized (2:1 ratio) to either Endo-HDR or standard external beam 
chemoradiation. 
 
14.2 Sample Size/Accrual Rate 
14.2.1 Sample Size and Power 
We will screen a total of 165 patients for the trial.  Based on our phase II single arm 
endorectal brachytherapy study, we expect approximately 20% of candidates will 
drop out because of unexpected findings on PET/CT (i.e. metastases) or MRI (i.e. 
iliac/inguinal lymph nodes). Therefore, we expect to randomize 138 patients in 2:1 
ratio into two treatment arms (92 in the Endo-HDR arm and 46 in the control arm).  
Using a one-sided Fisher’s exact test at significance level 0.1, we will have 80% 
power to detect a 17% increase of pathologic complete response rate from the 13% in 
the control treatment arm to 30% pCR in the Endo-HDR arm. After randomization, 
we expect <5% drop-out rate. 
 
One interim analysis for early assessment of futility is planned after 69 patients (half 
of the total planned sample size) have had their pCR evaluation. The trial will be 
terminated early if the ratio of the pCR rate in the Endo-HDR arm vs. control arm is 1 
or less, i.e., the Endo-HDR treatment appears the same or worse than the control 
treatment by any amount. This leads to minimal loss of power compared to an 
analysis without intermediate look. 
14.2.2 Accrual Rate 
Each center will enroll approximately 1 patient per month or 10-12 patients per year 
per site or approximately 60 patients total per year with six centers. With the appeal 
of a shorter treatment course and potential for decreased toxicity from radiotherapy, 
we are confident that we will accrue actively to meet our target goals. However, if we 
do not enroll 30 patients after 6 months, we will add additional sites. 
 


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14.3 Early Stopping Guidelines 
One interim analysis for early assessment of futility is planned after 69 patients (half of 
the total planned sample size) have had their pCR evaluation. The trial will be 
terminated early if the pCR rate in the Endo-HDR arm is less than the control group 
(standard chemoradiation).  If the pCR rate is the same or better with endorectal 
brachytherapy, the trial will continue. This leads to minimal loss of power compared to 
an analysis without an intermediate look. 
14.4 Analysis of Primary Endpoint 
The primary endpoint is pathologic complete response rate, which will be estimated for 
both arms as the proportion of patients who achieve pathologic complete response after 
the treatment. The corresponding 95% confidence intervals will be calculated. The 
comparison of pCR between the two arms will be performed using Chi-square test. The 
primary analysis of the pCR endpoint will be based on the intent-to-treat population 
which includes all randomized patients where patients are classified according to the 
randomized treatment assignment regardless of what treatment was received. 
14.5 Analysis of Secondary Endpoints 
Secondary endpoints of this phase II trial include toxicity, quality of life, locoregional 
control/distant metastasis, overall survival, and correlative analyses of biomarkers and 
functional imaging changes. 
 
The acute and chronic toxicity and adverse events will be summarized in frequency 
tables by type and grade for each arm and will be compared between arms using Fisher’s 
exact tests. 
 
Qualify of life will be assessed via EORTC QLQ-C30 (v3.0) questionnaires as 
mentioned above. Scoring will be based on procedures outlined by the EORTC. For our 
study population of rectal cancer patients, the analysis will be focused on general and 
colorectal model regarding urinary/bowel toxicity, sphincter function, and sexual 
dysfunction. For each module, summary statistics of the scores will be reported at 
baseline and each follow-up time. After confirming that there are no baseline differences 
in quality of life across the two treatment arms using independent samples t-test, 
changes in quality of life scores from pre- to post-treatment will be computed, and the 
difference between these change scores will be evaluated by paired-sample t-tests. We 
will compare the quality of life scores at each endpoint as well as the differences 
between the two arms using two-sample t-test. Given the plurality of comparisons, p-
values <0.01 will be considered statistically significant. In addition, mixed effect models 
will be used for assessing the quality of life change over time and comparing the two 
treatment arms. For instance, mixed effects models will be used to assess changes in 
QOL over time first in all study patients and then to compare the effects of the two 
treatment arms on change in QOL over time. Need for sexual aids will be compared in a 
descriptive fashion between the two cohorts. 
 


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Overall survival, distant metastases free survival, progression free survival, and local 
recurrence will be measured from the date of randomization to the date of death due to 
any causes. Patients last known to be alive are censored at date of last contact. Kaplan-
Meier curves will be used to characterize overall survival in each arm and log rank test 
will be used for the comparison.  
 
The analysis of correlative endpoints of imaging and biomarkers will be exploratory.   
 
For all patients in both study arms, the presence of VEGF/EGFR status will be assessed 
using pre-treatment tumor biopsies prior to the start of radiation therapy. The result will 
be expressed as a binary variable indicating the presence of expression 
(positive/negative). Its association with pCR will be assessed using Fisher’s exact test. 
We will also examine the role of VEGF/EGFR and other hypoxia related biomarkers as 
a predictive marker for tumor response following Endo-HDR treatment by testing the 
interaction of the treatment group and VEGF/EGFR status using a logistic regression 
model where pCR is the dependent variable.  
 
For those treated with Endo-HDR, we anticipate the pCR rate to be 40% among patients 
with favorable VEGF/EGFR and/or hypoxia marker signature compared to 10% pCR in 
the group with unfavorable signature. If we observe 40% patients with unfavorable 
profile, with 92 patients in the Endo-HDR arm, the test will have 89% power. 
 
T
a
b
l
e
 
2
Table 3. Power to detect a 30% difference  under various observed prevalence of  unfavorable 
VEGF/EGFR and/or hypoxia marker signatures using  a two-sided Fisher’s exact test at significance level 
0.05. 
 
To assess the correlation of functional PET/MR and treatment response, we will 
compare the change of SUV pre- and post-treatment between responders and non-
responders using a two-sample t-test. Non-parametric Wilcoxon test will be considered 
when the data are not normally distributed. For a binary response outcome, the 
predictive ability of the PET/MR marker will be evaluated using an ROC curve based on 
a logistic regression model in which the imaging marker will be entered as an 
independent variable.   
 
Prevalence of unfavorable signatures 
Power 
 
25% 
0.77 
40% 
0.89 
50% 
0.90 
75% 
0.85 


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63. Kojima M, Wakai K, Tokudome S, et al: Perceived Psychologic Stress and Colorectal Cancer 
Mortality: Findings From the Japan Collaborative Cohort Study. Psychosomatic Medicine 67:72-
77, 2005 
64. Cohen S, Kamarck T, Mermelstein R: A global measure of perceived stress. J Health Soc 
Behav 24:385-96, 1983 
65. Stephens RJ, Thompson LC, Quirke P, et al: Impact of Short-Course Preoperative 
Radiotherapy for Rectal Cancer on Patients' Quality of Life: Data From the Medical Research 


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Council CR07/National Cancer Institute of Canada Clinical Trials Group C016 Randomized 
Clinical Trial. Journal of Clinical Oncology 28:4233-4239, 2010 
66. Traa MJ, De Vries J, Roukema JA, et al: Sexual (dys)function and the quality of sexual life 
in patients with colorectal cancer: a systematic review. Annals of Oncology 23:19-27, 2012 
67. Herman JM, Narang AK, Griffith KA, et al: The Quality-of-Life Effects of Neoadjuvant 
Chemoradiation in Locally Advanced Rectal Cancer. International Journal of Radiation 
Oncology*Biology*Physics 85:e15-e19, 2013 
68. Rosen RC, Cappelleri JC, Gendrano N, 3rd: The International Index of Erectile Function 
(IIEF): a state-of-the-science review. Int J Impot Res 14:226-44, 2002 
69. Sand M, Rosen R, Meston C, et al: The female sexual function index (FSFI): a potential 
"gold standard" measure for assessing therapeutically-induced change in female sexual function. 
Fertility and Sterility 92:S129-S129, 2009 
70. Rosen R, Brown C, Heiman J, et al: The Female Sexual Function Index (FSFI): a 
multidimensional self-report instrument for the assessment of female sexual function. J Sex 
Marital Ther 26:191-208, 2000 
71. Rosen RC, Riley A, Wagner G, et al: The international index of erectile function (IIEF): a 
multidimensional scale for assessment of erectile dysfunction. Urology 49:822-30, 1997 
72. Flynn KE, Lin L, Cyranowski JM, et al. Development of the NIH PROMIS® Sexual Function 
and Satisfaction Measures in Patients with Cancer. Journal of Sexual Medicine. 2013;10: 43-52). 


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APPENDIX I: SKCCC DSMP I 
 
This is a DSMP Level I study under the SKCCC Monitoring Plan. A Level I study requires both 
internal and external data monitoring. The Principal Investigator is responsible for internal 
monitoring for both safety and data quality. External data monitoring will be performed by the 
SKCCC at Johns Hopkins Clinical Research Office Quality Assurance Program (CRO QA). 
 
Data and safety monitoring oversight will be conducted by the SKCCC at Johns Hopkins Safety 
Monitoring Committee. Per the SKCCC at Johns Hopkins Safety Monitoring plan, the CRO QA 
will forward summaries of all monitoring reports to the Safety Monitoring Committee for 
review. All reportable anticipated and unanticipated protocol events/problems and amendments 
that are submitted to the IRB will also be reviewed by the Safety Monitoring Committee Chair 
(or designee) and QA manager. 
 


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APPENDIX II: PARTICIPATING SITE GUIDELINES 
 
This study will be conducted in accordance with the Sidney Kimmel Comprehensive Cancer 
Center’s Coordinating Center Protocol. 
 
Patient Registration 
Prior to protocol enrollment and initiation of treatment, subjects must sign and date an IRB 
approved consent form.  All patients must be registered centrally at the Sidney Kimmel 
Comprehensive Cancer Center.  
To register a patient, the following documents must be completed and faxed (443-287-8354) or 
e-mailed to the Coordinating Center: 
 Signed patient consent form 
 Registration Form 
 
Copies of pertinent lab results, pathology reports, etc. (please specify what 
source documents are required to confirm eligibility, if applicable) 
 
The Coordinating Center will review the documents to confirm eligibility.  To complete the 
registration process, the Coordinating Center will: 
 assign a patient study number 
 register the patient on the study with the Sidney Kimmel Comprehensive 
Cancer Center’s Clinical Research Office 
 
fax or e-mail the patient study number to the participating site. 
 
Multicenter Guidelines 
 
 
Protocol Chair 
 
The Protocol Chair is responsible for performing the following tasks: 
 Coordinating, developing, submitting, and obtaining approval for the protocol as well 
as its subsequent amendments. 
 Assuring that all participating institutions are using the correct version of the 
protocol. 
 Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study. 
 Reviewing and ensuring reporting of Serious Adverse Events (SAE) 
 Reviewing data from all sites. 
 
 
Coordinating Center 
 
The Coordinating Center is responsible for performing the following tasks: 
 Ensuring that IRB approval has been obtained at each participating site prior to the 
first patient registration at that site, and maintaining copies of IRB approvals from 
each site. 
 Managing central patient registration. 
 Collecting and compiling data from each site. 


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 Establishing procedures for documentation, reporting, and submitting of AE’s and 
SAE’s to the Protocol Chair, and all applicable parties. 
 Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites. 
 
 
Participating Sites 
 
Participating sites are responsible for performing the following tasks: 
 Following the protocol as written, and the guidelines of Good Clinical Practice 
(GCP). 
 Submitting data to the Coordinating Center. 
 Registering all patients with the Coordinating Center by submitting patient 
registration form, and signed informed consent promptly. 
 Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the protocol. 
 Maintaining regulatory binders on site and providing copies of all required documents 
to the Coordinating Center. 
 
Collecting and submitting data according to the schedule specified by the protocol. 
 
Quality Assurance 
This is a Level I study under the SKCCC Data Safety Monitoring Plan.  Data Monitoring of this 
protocol will occur on a regular basis with the frequency dependent on the rate of subject accrual 
and the progress of the study.  The protocol will be monitored internally at SKCCC by Dr. Amol 
Narang weekly and externally by the SKCCC CRO in accordance with SKCCC guidelines.  Trial 
monitoring and reporting will be done through the Safety Monitoring Committee at SKCCC. 
 
Authorized representatives of the Coordinating Center may visit participating sites to perform 
audits or inspections, including source data verification.  The purpose of these audits or 
inspections is to systematically and independently examine all trial related activities and 
documents to determine whether these activities were conducted and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice (GCP), and 
any applicable regulatory requirements. 
 
Data Submission 
Data and/or completed case report forms must be transmitted by facsimile report, email, or 
internet database to the Coordinating Center monthly. Case report forms will be provided to 
participating sites by the Coordinating Center. 
 
Adverse Event Reporting 
 
 
Definition of Adverse Event (AE) 
An adverse event is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product.  An 
undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory 
findings, electrocardiogram).  In clinical trials, from the time of signing an informed 


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consent, an AE can include an undesirable medical condition occurring at any time, 
including run-in or washout periods, even if no trial treatment has been administered. 
 
Definition of Serious Adverse Event (SAE) 
A serious adverse event is an AE occurring during any trial phase (i.e., run-in, treatment, 
washout, follow-up), and at any dose of the investigational product, comparator or 
placebo, that fulfills one or more of the following criteria: 
 Results in death 
 Is immediately life-threatening 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Is a congenital abnormality or birth defect 
 Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above 
 
Protocol Chair 
The Protocol Chair is ultimately responsible for the required reporting of all adverse 
events. 
 
Coordinating Center 
The Coordinating Center is the central location for the collection and maintenance of 
documentation of adverse events and is responsible for submitting adverse event reports 
to the Protocol Chair promptly.  The Coordinating Center will maintain documentation of 
all adverse event reports for each participating site.  Adverse event reports submitted to 
the Coordinating Center must be signed and dated by the participating site’s Principal 
Investigator.  The Coordinating Center will provide appropriate forms to be used by all 
participating sites for reporting adverse events.  Information to be provided must include: 
 Subject ID number, and initials 
 Date of the event 
 Description of the event 
 Description of site's response to the event 
 Assessment of the subject's condition 
 Subject's status on the study (on study, off study, etc.) 
 Attribution of event to study drug 
 
Participating Sites 
Participating sites are responsible for reporting adverse events to their IRB according to 
its specific requirements and to the Coordinating Center as follows: 
 
Fatal Events whether anticipated or unanticipated, and whether or not related to the 
study must be reported to the Coordinating Center within 24 hours of the 
participating site Principal Investigator's learning of the event. 
 


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Serious and Unanticipated Adverse Events as defined above must be reported to 
the Coordinating Center within 24 hours of the participating site Principal 
Investigator's learning of the event.  
 
Other Serious Adverse Events which may result in a change to the protocol, 
informed consent, or risk to subjects as specified in the protocol must be reported 
within three (3) working days of the participating site Principal Investigator's 
learning of the event.  
 
Adverse Events which result in no change to protocol, informed consent, or risk to 
subjects must be reported to the Coordinating Center on a monthly basis.  
 
Adverse event reports are to be faxed to the Coordinating Center at 443-287-1889. 
Follow-up reports are faxed, mailed, or sent electronically to the Coordinating Center 
as necessary. 
 
The investigator must also report follow-up information about SAEs within the same 
time frames. 
 
If a non-serious AE becomes serious, this and other relevant follow-up information 
must also be provided within the same time frames described above. 
 
All SAEs must be collected whether or not they are considered causally related to the 
investigational product.  Investigators and other site personnel are responsible for 
reporting all casually related SAEs to their IRB and the Protocol Chair. 
 


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APPENDIX III: Neoadjuvant Endo-HDR Quality Criteria 
 
Major Violation Criteria 
1. Geographic miss of the tumor bed  
2. Loading error during the treatment 
3. Inability to reproduce the planning position of the catheter during the treatment 
4. Rectal perforation 
 
Minor violation Criteria 
1. 
Tight or generous tumor margins 
2. 
Minor deviation (less than 1cm ) in the daily loading prescription 
 
Medical Physicist 
1. 
Inappropriate assignment of the first dwell position on the planning CT data set (more 
than 2 x slice thickness) 
2. 
More than 5% of the target volume outside from the prescription isodose cloud 
3. 
Inadvertent use of the step size during the treatment as compared to the planning 
(example: plan performed with 2.5 mm step size and treatment delivered with 5.0 mm 
step size) 
4. 
Loading the daily treatment in the opposite direction with respect to the daily 
prescription (example: daily Rx is to load 1 cm above and the treatment is loaded 1 cm 
below the reference dose distribution) 
5. 
Improper channel assignment during a daily treatment 
6. 
Inappropriate assignment of the channel rotational position (more than ±5o, or more than 
1.5 mm misalignment between x-ray markers in channels 1 and 5 as seen on a daily 
radiograph) 
 


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APPENDIX IV: Tumor Regression Definition 
 
Grade 0: no regression 
Grade 1: minor regression (dominant tumor mass with obvious fibrosis in 25% or less of the 
tumor mass) 
Grade 2: moderate regression (dominant tumor mass with obvious fibrosis in 26 to 50% of the 
tumor mass) 
Grade 3: Good regression (dominant fibrosis outgrowing the tumor mass; i.e., more than 50% 
tumor regression) 
Grade 4: Total regression (no viable tumor cells, only fibrotic mass). 
 
 
Ref: Rodel C. Prognostic Significance of tumor regression after preoperative chemoradiotherapy 
for rectal cancer. Journal of Clinical Oncology. 2005,23 8688-8696 
 
 
Versus  
 
Grade 1: No fibrosis with extensive residual cancer or single cells or small groups of cancer 
cells 
Grade 2. Residual cancer outgrown by fibrosis 
Grade 3. No viable cancer cells or single cells or small groups of cancer cells. 
 
 
Ref: R. Ryan. Pathological response following long course neoadjuvant chemoradio-therapy for 
locally advanced rectal cancer. Histopathology 2005.47,141-146. 
 


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APPENDIX V: Quality of TME 
Poor surgery
little mesorectum
1
Average surgery with
incomplete removal of
mesorectum
2
Excellent surgery with
complete mesorectal
excision 
3
 


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APPENDIX VI: Intra-Operative Data Collection 
 


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APPENDIX VI: Quality of Life Assessments 
 
 
Marital/Partnered Status 
 
a. Marital status: What is your current marital status? 
i. Married 
ii. Living with partner, not married 
iii. In a significant relationship but not living together 
iv. Widowed and not currently in a relationship 
v. Divorced and not currently in a relationship 
vi. Single, never married 


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 Treatment-Related Stress 
 
A. Individual items assessing treatment-related stress and impact on daily life.  
 
1. In the last month, how many days of work have you missed because of your cancer treatment?  
[0 days; 1-2 days; 3-4 days; 4-6 days; a week or more; not applicable because wasn’t 
working] 
 
2. Overall, how much has your cancer treatment interfered with your daily life? 
[0=Not at all; 1=A little bit; 2=Somewhat; 3=Much; 4= Very much] 
 
3. Overall, how much has your cancer treatment caused you stress (e.g., hassles)? 
[0=Not at all; 1=A little bit; 2=Somewhat; 3=Much; 4= Very much] 
 
4. In the last month, how much has your cancer treatment interfered with your ability to do your 
work (including work at home)? 
[0=Not at all; 1=A little bit; 2=Somewhat; 3=Much; 4= Very much] 
 
5. In the last month, how much has your cancer treatment interfered with your ability to 
participate in social activities (e.g., go to church; spend time with friends or family)? 
[0=Not at all; 1=A little bit; 2=Somewhat; 3=Much; 4= Very much] 
 
6. In the last month, how much has your cancer treatment interfered with your ability to engage 
in enjoyable activities with your spouse/partner or friends? (e.g., go out to dinner) 
[0=Not at all; 1=A little bit; 2=Somewhat; 3=Much; 4= Very much] 
 
7. Overall, do you feel stress during your daily life? 
[1=Little or none; 2=Moderate; 3=High; 4=Extreme] 
 


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B. The Perceived Stress Scale* 
 
*Scoring for each item is given below. 
STRESS 
Perceived Stress Scale  
The questions in this scale ask you about your feelings and thoughts 
during the last month. In each case, you will be asked to indicate by 
circling how often you felt or thought a certain way. 
Never 
Almost 
Never 
Sometimes 
Fairly 
Often 
Very 
Often 
1. In the last month, how often have you been upset because of something 
that happened unexpectedly? 
0 
1 
2 
3 
4 
2. In the last month, how often have you felt that you were unable to 
control the important things in your life? 
0 
1 
2 
3 
4 
3. In the last month, how often have you felt nervous and “stressed”? 
0 
1 
2 
3 
4 
4. In the last month, how often have you felt confident about your ability 
to handle your personal problems? 
4 
3 
2 
1 
0 
5. In the last month, how often have you felt that things were going your 
way? 
4 
3 
2 
1 
0 
6. In the last month, how often have you found that you could not cope 
with all the things that you had to do? 
0 
1 
2 
3 
4 
7. In the last month, how often have you been able to control irritations in 
your life? 
4 
3 
2 
1 
0 
8. In the last month, how often have you felt that you were on top of 
things? 
4 
3 
2 
1 
0 
9. In the last month, how often have you been angered because of things 
that were outside of your control? 
0 
1 
2 
3 
4 
10. In the last month, how often have you felt difficulties were piling up 
so high that you could not overcome them? 
0 
1 
2 
3 
4 


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Sexual Relationship Screener 
 
Are you in a relationship that could involve sexual activity? 
 
 No 
 Yes 
 
In the past 30 days 
Have you had any type of sexual activity with another person (including your partner) 
 
 No 
 Yes 
 
Are you… 
 Male 
 Female 
 Other 
 


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Sexual Activity Items 
 
PROMIS 
Item Number 
Item Wording 
Response Options 
Items for Women 
In the past 30 days  
SFAID101 
How often have you used personal lubricants 
(such as KY Jelly or Astroglide) for sexual 
activity? 
0=Have not had any sexual activity in the 
past 30 days 
1=Never 
2=Rarely 
3=Sometimes 
4=Often 
5=Always 
SFAID102 
How often have you used vaginal moisturizers 
(such as Replens)? 
1=Never 
2=Rarely 
3=Sometimes 
4=Often 
5=Always 
SFAID103 
Have you used hormones (for example, 
estrogen, testosterone, or progesterone) for 
sexual activity either as a patch on your skin, or 
a cream, tablet, or ring inserted into your 
vagina?  
1=No 
2=Yes 
0=I don’t know 
SFAID104 
Have you used a vaginal dilator? 
1=No 
2=Yes 
0=I am not sure what a vaginal dilator is 
Items for Men 
In the past 30 days 
SFAID105 
How often have you taken a pill such as Viagra, 
Cialis, or Levitra for sexual activity? 
1=Never 
2=Rarely 
3=Sometimes 
4=Often 
5=Always 
SFAID106 
Have you taken testosterone for sexual activity? 
1=No 
2=Yes 
0=I don’t know 
SFAID107 
How often have you used an injection into your 
penis to get an erection? 
1=Never 
2=Rarely 
3=Sometimes 
4=Often 
5=Always 
SFAID108 
How often have you used a vacuum pump 
(penis pump) to get an erection? 
1=Never 
2=Rarely 
3=Sometimes 
4=Often 
5=Always 
 


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APPENDIX VII: Imaging Techniques/Central Image Review 
 
MRI Imaging Guidelines 
 
1) All imaging will be electronically transferred according to the IRAT guidelines.  See 
appendix for specific information.  All MRS and MRI sequences will be performed on the 
same scanner when possible (3.0T field strength) to ensure high repeatability and minimal 
variability between MR scans. Dedicated research MR technicians will be trained specifically for 
our protocol and MR parameters will be standardized for this study to minimize variability 
further.  During the course of the trial, a quality assurance phantom will be scanned bi-weekly to 
ensure that the MR unit is functioning properly for the acquisition of reproducible data.  An MRI 
will be performed before and 8 weeks following Endo-HDR.  T2-weighted images, diffusion-
weighted images, dynamic perfusion images and subtracted dynamic images will be interpreted 
side by side to facilitate anatomic localization. For diffusion weighted imaging the apparent 
diffusion coefficient values (ADC) will be calculated from the low and high b-value images 
according to the formula; ADC = [ln (Sh/Sl)]/(bh-bl), where Sh and Sl are signal intensities in 
the region/volume of interest obtained with low and high b values, respectively.  
  
At baseline and 8 weeks following Endo-HDR we will perform a subjective local tumor and 
nodal staging.  A confidence level scoring system will be used for T-staging and nodal 
morphology, and heterogenicity will be used for N-staging. The confidence levels will be set at: 
tumor definitely absent (complete intact muscular layer)=CR, probably absent (partial disruption 
of the muscular layer without extension of tumor beyond the contour of the rectal wall), probably 
present (complete disruption of the muscular rectal wall with mild bulging tumor margin) and 
definitely present (complete disruption of the muscular rectal wall with tumor invasion of the 
perirectal fat). Tumors will be classified as T1 when they are confined to the submucosa, T2 
when it invades, but does not penetrate the muscularis propria, T3 when it penetrates the 
muscularis propria and T4 when it invades adjacent organs including the pelvic wall or visceral 
peritoneum.  For nodal status, morphology and heterogenicity will be used for differentiating 
malignant and non-malignant lymph nodes (LN).  Nodes with a smooth, well-defined margin and 
homogeneous intensity will be grouped as nonmalignant LN. Nodes with an irregular or 
spiculated contour, indistinct margin and mottled heterogeneous intensity will be grouped as 
malignant LN. The TNM classification system will be used for nodal staging as follows: N0, no 
malignant nodes; N1, 1-3 malignant nodes; or N2, >4 malignant nodes. All MRI data analysis 
will be performed by Dr. Kamel, a clinical gastrointestinal radiologist with vast experience, who 
will be blinded to other clinical or histopathological information. MR measurements after 
neoadjuvant treatment will be performed mirroring the baseline analysis. Baseline MR images 
and scoring will be co-registered to post-treatment images to obtain voxelwise comparison of the 
MR measurements. Should it not be possible to co-register the tumors, due to extreme size 
change or deformation, post-treatment and baseline images will be analyzed side by side to 
ensure that comparable volumes of interest are being analyzed at each time point. Further 
imaging of the participant will be at the discretion of the treating physician. 
  
2) As part of the MRI acquisition and to gain data from the use of functional aspects of the MRI, 
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Diameter and volume of the tumor will be measured. The volume of interest will be analyzed on 
all sequences to provide the various multiparametric MR measurements (e.g. ADC, % 
perfusion). 
  
3) Spectral data will be processed on a dedicated workstation, aligned with the corresponding 
MR images by using voxel-shifting and baseline phase-correcting tools available with the point-
resolved spectroscopy sequence package and archived as an array of spectral data (including 
automated estimates of the choline plus creatine-to-citrate ratio and the choline-to-creatine ratio) 
with the corresponding MR images in Digital Imaging and Communications in Medicine format. 
Peak area ratios will be calculated by means of integration of the metabolite peak over a fixed 
frequency range defined in a peak file containing peak positions and widths. With use of an MR 
spectroscopic imaging overlay sheet and pre-established criteria for the probability of 
malignancy based on the choline plus creatine-to-citrate ratio and the choline-to-creatine ratio, 
the location and size of areas suspicious for cancer will be determined and the type and total 
number of abnormal voxels will be recorded for each lesion depicted at MR spectroscopic 
imaging at baseline and during post-treatment assessment.  Spectral data will be obtained from 
Johns Hopkins patients only. 
  
PET-CT Imaging Guidelines 
 
Participants will undergo a FDG-PET/CT (diagnostic CT) before and 8 weeks after Endo-HDR 
using standard JHU protocols. Specifically, a 4-hour fast will be required prior to the 
examination, although water intake is allowed. A blood glucose level will be checked in patients, 
and the study will not be performed if the blood glucose exceeds 150 mg/dL. Participants are 
initially injected with 15 to 20 mCi of FDG intravenously and then instructed to drink oral CT 
contrast lacking glucose with a 13% barium concentration. Imaging will take place in the supine 
position from the skull base to the mid thigh with the GE Discovery LSFDG- PET/CT system 
(GE Medical Systems, Milwaukee, WI, or similar machines at participating subsites). 
Simultaneous diagnostic IV/oral contrast CT images will be obtained generally at 140 kV, 80 
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APPENDIX VII: Performance Status 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 


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Protocol Chair:  Amol Narang, M.D.  
Version 7.0  May 19, 2020 
 
 
89 
 
APPENDIX IX: AJCC Staging 
 
A. Primary Tumor 
 
pTX 
Primary tumor cannot be assessed 
 
pT0 
No evidence of primary tumor 
 
 
pTis 
Carcinoma in situ and intramucosal carcinoma (high grade dysplasia) 
 
pT1 
Tumor invades submucosa 
 
pT2 
Tumor invades muscularis propria 
 
pT3 
Tumor invades through the muscularis propria into  
 
 
subserosa or into nonperitonealized pericolic or perirectal tissue 
pT4a Tumor invades other organs or structures  
pT4b Tumor perforates the visceral peritoneum 
 
B. Regional Lymph Nodes 
 
pNX Regional lymph nodes cannot be assessed 
 
pN0 
No regional lymph node metastasis 
 
pN1 
Metastasis in 1 to 3 regional lymph nodes 
 
pN2 
Metastasis in 4 or more regional lymph nodes 
 
C. Distant Metastasis 
 
 
pMX Cannot be assessed 
 
 
pM0 No distant metastasis 
pM1 Distant metastasis 
 
 
Reference: 
 
AJCC Cancer Staging Manual.  Lippincott-Raven Press, 6th edition, 2002.