Clinical trial NCT02319304
Conditions: Rectal Adenocarcinoma
Keywords: Pelvic Radiotherapy Rectal Adenocarcinoma
Sponsor: University of Maryland, Baltimore
Start date: 2015-03-01; Completion date: 2018-10-05
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the effects, both good and bad, of adding very low dose fractionated radiation therapy (LDFRT) to the pelvis, with FOLFOX chemotherapy prior to surgery. Standard pelvic radiation therapy given once a day (Monday through Friday) over approximately 5.5 weeks is not given in this study. You will receive 6 cycles of FOLFOX (each cycle is 2 weeks) and you will also get an LDFRT to your pelvis given twice a day on the first two days of each cycle.

Detailed description:
The current standard of care for treatment of locally advanced rectal cancer consists of neoadjuvant whole pelvic RT with radiosensitizing single-agent 5-FU followed by surgery and adjuvant full dose chemotherapy (typically FOLFOX). For all clinical T3, T4, and/or lymph node positive rectal cancer patients the standard neoadjuvant radiation dose per fraction is 180 cGy delivered on consecutive weekdays over 5.5 weeks for a total of 5040 cGy. A potentially paradigm-changing approach is currently being investigated in a phase II/III trial in which neoadjuvant RT is omitting in favor of using full dose FOLFOX chemotherapy based on provocative data published from Memorial Sloan Kettering Cancer Center. We hypothesize that whole pelvic LDFRT using 40 cGy fractions for a total of 960 cGy can be safely added concurrently to neoadjuvant full dose FOLFOX as an alternative to standard neoadjuvant 5-FU chemoradiation. We further hypothesize that using LDFRT as a chemopotentiatior will significantly increase the pCR rate as reported by the Memorial Sloan Kettering pilot study of 27%. Lastly, due to the significantly lower radiation dose per fraction and lower total radiation dose we expect that this novel strategy will not cause higher rates of severe toxicity compared to neoadjuvant FOLFOX alone.

Specifically, this phase II trial intends to determine whether 6 cycles of neoadjuvant FOLFOX with concurrent LDFRT followed by comprehensive restaging and TME achieves favorable outcomes for patients with T3N0M0, T3N1M0, or T2N1M0 rectal cancer. As mentioned above, the current standard of care for all locally advanced rectal cancer patients includes radiosensitizing 5-FU and concurrent whole pelvic RT to 5040 Gy in 180 Gy once daily fractions. Per the proposed protocol, T3N0M0, T3N1M0, or T2N1M0 rectal cancer patients who are eligible to undergo a low anterior resection would receive whole pelvic RT to 960 cGy in 40 cGy fractions delivered twice daily on days 1-2 of each cycle of FOLFOX chemotherapy for a total of 6 cycles.

Eligible study subjects include adults who are candidates for curative intent sphincter-sparing surgery and who lack high-risk features, particularly tumor encroaching upon the mesorectal fascia (within 3 mm) as determined by pre-treatment endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI) or distal rectal tumors (\<5 cm from the anal verge).

Arms: arm 1: Part I:

FOLFOX: combination of drugs administered in a specific sequence as prescribed below.

* Oxaliplatin: 85 mg/m2 intravenously (IV) over 2 hours
* Leucovorin: 200 mg/m2 IV bolus over 2 hours
* 5-FU: 400 mg/m2 IV bolus over 5-15 minutes, then 2,400 mg/m2 continuous IV infusion over 46-48 hours

Part II:

Low dose fractionated radiation therapy (LDFRT) Intensity-modulated, bone marrow sparing, whole pelvic radiation therapy 40 cGy fractions twice per day delivered at least 4-6 hours apart on the first 2 days of each chemotherapy cycle for a total of 6 cycles
Interventions: intervention 1: FOLFOX {5-fluorouracil (5-FU), leucovorin, and oxaliplatin} intervention 2: Low dose fractionated radiation therapy (LDFRT)
Intervention descriptions: intervention 1: see arm description intervention 2: see arm description

Protocol documents:
Prot_SAP_000.pdf: 
 
 
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GCC 1314 
(HP-00060641) 
NCT02319304 
 
Phase II Trial of Low Dose Whole Pelvic Radiotherapy with Concurrent 
Neoadjuvant FOLFOX for Patients with Newly Diagnosed T3N0M0, T2N1M0, or 
T3N1M0 Rectal Adenocarcinoma 
 
Principal Investigator   
Adeel Kaiser, MD 
Assistant Professor, Department of Radiation Oncology 
University of Maryland School of Medicine 
22 South Greene Street 
Baltimore, MD 21201 
(401) 328-2328 
adeelkaiser@umm.edu 
 
 
Co-Principal Investigators 
William Regine, MD 
Professor, Division of Radiation Oncology 
University of Maryland School of Medicine 
Baltimore, MD 21201 
(410) 328-2326 
wregine@umm.edu 
 
Nader Hanna, MD 
Professor of Surgery, Division of Surgical Oncology 
University of Maryland School of Medicine 
Baltimore, MD 21201 
(410) 328-7320 
nhanna@smail.umaryland.edu 
 
Yixing Jiang, MD 
Associate Professor, Division of Medical Oncology 
University of Maryland School of Medicine 
Baltimore, MD 21201 
(410) 328-7225 
yjiang@umm.edu 
H. Richard Alexander, MD 
Professor of Surgery, Division of Surgical Oncology 
University of Maryland School of Medicine 
Baltimore, MD 21201 
(410) 328-5109 
hralexander@smail.umaryland.edu 
 
Petr Hausner, MD, PhD 
Associate Professor, Division of Medical Oncology 
University of Maryland School of Medicine 
Baltimore, MD 21201 
(410) 328-2567 
phausner@umm.edu 
 
Naomi Horiba, MD 
Associate Professor, Division of Medical Oncology 
University of Maryland School of Medicine 
Baltimore, MD 21201 
(410) 328-3689 
mhoriba@umm.edu 
 
Statistician 
Alexandra Hanlon, PhD 
Research Associate Professor of Nursing 
University of Pennsylvania School of Nursing 
Philadelphia, PA 19104 
(215) 898-4581 
alhanlon@nursing.upenn.edu 
Clinical Research Associates   
Wanda Bell-Farrell, RN, MS 
Department of Radiation Oncology 
University of Maryland School of Medicine 
Baltimore, MD 21201 
(410) 328-8018 / 6472 
akudryashev@umm.edu 
wandabellfarrell@umm.edu 
 
 
 
 
 
 
 
 
 


 
 
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TABLE OF CONTENTS 
 
 
Section 
Title 
 
Abbreviations 
 
Schema 
1.0 
Background 
2.0 
Objectives 
3.0 
Eligibility 
4.0 
Registration 
5.0 
Treatment Plan 
6.0 
Restaging 
7.0 
Surgery 
8.0 
Pathological Tumor Assessment 
9.0 
Adjuvant therapy 
10.0 
Data Safety Monitoring and Adverse Event Monitoring and Reporting 
11.0 
Dose Modification Based on Adverse Events 
12.0 
Patient Discontinuation 
13.0 
Pharmacology 
14.0 
Statistics 
Appendix I 
Study Schedule 
Appendix II 
ECOG Performance Status 
Appendix III 
NCI CTCAE version 4.0 
Appendix IV 
AJCC Staging 7th Edition 
 
References 
 
 


 
 
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SCHEMA 
 
T3N0M0, T2N1M0, or T3N1M0 Rectal Adenocarcinoma 
 
 
 
FOLFOX: 5-fluorouracil (5-FU), leucovorin, and oxaliplatin  
Oxaliplatin: 85 mg/m2 intravenously (IV) over 2 hours 
Leucovorin: 200 mg/m2 IV bolus over 2 hours 
5-FU: 400 mg/m2 IV bolus over 5–15 minutes, then 2,400 mg/m2 continuous IV 
infusion over 46-48 hours 
 
Low dose fractionated radiation therapy (LDFRT) 
Intensity-modulated, bone marrow sparing, whole pelvic radiation therapy 
40 cGy fractions twice per day delivered at least 4–6 hours apart on the first 2 
days of each chemotherapy cycle for a total of 6 cycles 
 
 
Day 1 
Day 2 
Oxaliplatin 
 
 
Leucovorin 
 
 
5-FU 
 
 
LDFRT 
 (each fraction 
separated by a 
minimum of 4 
hours) 
(each fraction 
separated by a 
minimum of 4 
hours)) 
 
Primary Objective: To determine whether the addition of concurrent LDFRT to 
neoadjuvant full dose FOLFOX results in a pCR response rate of at least 35%. 
 
Secondary Objective: To assure that neoadjuvant concurrent LDFRT-FOLFOX 
maintains a high rate of pelvic R0 resection compared to standard preoperative 
chemoradiation and total mesorectal excision surgery. 
 
Accrual Goal: 30 patients.
Histologically confirmed 
clinical T3N0M0, 
T2N1M0, and T3N1M0 
rectal adenocarcinoma 
FOLFOX x 6 cycles 
+ concurrent 
LDFRT  
(1 cycle = 2 weeks) 
Restage 
Low anterior 
resection with 
total 
mesorectal 
excision 
 
Adjuvant therapy per 
physician discretion 


 
 
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1.0  BACKGROUND 
 
1.1  Potential Role for Decreased-Intensity Neoadjuvant Therapy for Locally 
Advanced Rectal Cancer Patients Undergoing Low Anterior Resection with Total 
Mesorectal Excision (TME). 
It is estimated that about 40,000 new cases of rectal cancer are diagnosed in the U.S. 
annually, and these are expected to result in approximately 22,000 deaths1.  Treatment 
for locally advanced (T3/T4/N+) rectal cancers has evolved over the course of several 
decades.  Before 1990, surgery alone without total mesorectal excision (TME) was the 
accepted standard of care for stage II and III rectal cancers.  However, this approach 
was found to be suboptimal because of high local recurrence rates of greater than 50%.  
In an attempt to decrease local recurrences, which commonly cause significant 
morbidity, investigators conducted trials asking whether adjuvant 5-FU-based 
chemotherapy and radiation therapy provided any benefit.  The Gastrointestinal Tumor 
Study Group 9173 (GITSG 9173) and North Central Cancer Treatment Group (NCCTG) 
trials in particular showed a significant decrease in local recurrence following adjuvant 
chemoradiation compared with observation2,3.  These data led to a 1990 consensus 
statement being issued by the National Cancer Institute (NCI) recommending that 
surgery followed by adjuvant chemotherapy and radiation therapy (RT) should become 
the new standard of care4. 
 
Several randomized trials also evaluated the role of neoadjuvant RT for locally 
advanced rectal cancer.  At least in theory, neoadjuvant therapies have several 
advantages over postoperative therapies including better tumor oxygenation and 
smaller radiation treatment ports.  The Swedish and Dutch Rectal Cancer trials both 
randomized patients to short-course neoadjuvant RT (25 Gy in 5 fractions) without 
concurrent chemotherapy5,6.  Notably, patients in the Swedish trial did not undergo TME 
while those in the Dutch trial did receive TME.  These trials collectively demonstrated a 
local control benefit for both neoadjuvant short-course radiotherapy and TME. 
 
Although both neoadjuvant and postoperative treatment strategies were shown to 
provide a local control, the current standard of care for stage II and III rectal cancers is  
neoadjuvant chemoradiation, based on data published from the German Rectal Study 
Group. Sauer et al. compared neoadjuvant with postoperative chemoradiation (50.4 Gy 
plus continuous infusion 5-FU) in 823 patients with resectable rectal cancer7.  
Neoadjuvant therapy had several benefits over postoperative chemoradiation including 
a lower 5-year local recurrence rate (6% and 13%, respectively; P = 0.006), less acute 
and late toxicity, and a higher percentage of sphincter-preserving surgeries in patients 
who were initially scheduled for an abdominoperineal resection (APR).   No differences 
were found in the frequency of distant metastases or in overall survival. An 8% 
pathologic complete response rate (pCR) was observed in the neoadjuvant arm.  The 
NSABP R-03 trial also prospectively compared preoperative to postoperative 
chemoradiation in a randomized fashion8.  Although it closed early because of poor 
accrual, this trial confirmed a benefit in favor of neoadjuvant therapy.  After a median 
follow up of 8.4 years, the neoadjuvant arm had improved 5-year disease-free survival 
without a significant difference in overall survival.  The pCR rate in the neoadjuvant arm 


 
 
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was 15%.  Thus, preoperative pelvic chemoradiation followed by TME-based resection 
is now the standard of care for locally advanced rectal cancer.  Based on data 
extrapolated from colon cancer, these patients are also routinely recommended to 
receive adjuvant 5-FU-based chemotherapy. 
 
This proposed study does not seek to introduce novel treatment agents.  Instead, it 
aims to make modifications in standard-of-care trimodality therapy intended to maintain 
excellent long-term outcomes while potentially decreasing significant treatment-related 
toxicity.  The rationale for this concept stems from a confluence of factors related to 
contemporary management of locally advanced rectal cancer. 
 
1.1.1  Neoadjuvant RT with standard pelvic RT doses may result in overtreatment 
of some patients. 
Although neoadjuvant chemoradiation reduces toxicity compared to adjuvant 
chemoradiation, the potential remains for a minority of patients to demonstrate 
significant acute and/or late adverse effects.  This has resulted in debate regarding 
whether all locally advanced rectal cancer patients should receive the same intensive 
neoadjuvant treatment regimen.9  Some centers have suggested eliminating RT in 
patients with more favorable disease who are at a lower risk of local recurrence, 
especially in the era of TME.10-12  Because of the lack of data supporting a 
chemotherapy-only approach, neoadjuvant chemoradiation remains the standard of 
care for all locally advanced rectal cancer patients. 
 
1.1.2  Standard pelvic RT doses are associated with both short and long-term 
morbidity. 
Standard neoadjuvant chemoradiation can result in considerable acute toxicity, which is 
seen in up to 50% of patients.13  Treatment time is also substantial in that it requires 28 
daily radiation treatments over 5.5 weeks as well as additional visits to receive either 
oral or intravenous 5-FU.  Most importantly, the late effects of pelvic radiation can be 
significant, including fibrosis and autonomic nerve injury and may be accompanied by 
increased fecal incontinence, urgency/frequency, and higher rates of bladder and 
sexual dysfunction when compared to patients that do not receive pelvic radiation.7,14,15  
In addition, because the pelvis is an active site of hematopoiesis, patients who undergo 
pelvic radiation may have diminished ability to withstand subsequent myelosuppressive 
therapy, a consideration that is more relevant in an era in which a greater number of 
chemotherapeutic options are available for metastatic disease.  Pelvic fracture after 
modest trauma such as an uncomplicated fall also occurs more commonly in patients 
after pelvic irradiation with standard RT dosing.16 
 
1.1.3 Neoadjuvant radiation delays initiation of full dose systemic therapy. 
Current rectal cancer treatment paradigms do not deliver full dose systemic 
chemotherapy such as FOLFOX until 14-18 weeks from initiation of neoadjuvant 
chemoradiotherapy and this delay is potentially disadvantageous because it allows a 
window for metastatic dissemination of disease.  The standard treatment timeline is as 
follows: 5.5 weeks of neoadjuvant chemoradiation; 4-6 weeks recovery; surgical 
resection; 4-6 weeks postoperative recovery; and then initiation of adjuvant therapy.  As 


 
 
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a result, no full dose chemotherapy is delivered to treat potential micrometastases until 
more than 3 months after treatment onset.  The delay in full-dose systemic therapy may 
open a window of opportunity for growth of small-volume disease outside the pelvis.  
Our hypothesis is that delivering full dose chemotherapy such as FOLFOX earlier in the 
treatment course may decrease the likelihood of disease dissemination outside of the 
pelvis. 
 
1.1.4  Advancements in systemic therapy and surgical techniques have 
substantially improved outcomes over the last decade. 
Local control is critically important because of the high morbidity associated with pelvic 
recurrence. Traditional surgery, now outmoded, involved blunt digital dissection of the 
mesorectum and often resulted in tearing the mesorectal fascia and/or incomplete 
resection of the nodal basin around the rectum with a positive radial margin. In this 
setting, postoperative chemoradiation reduced local recurrence by sterilizing tumor 
deposits left in the pelvis from inadequate surgery. The introduction and acceptance of 
TME and subsequent standardization of sharp dissection of the lymph node–bearing 
tissue resulted in low positive radial margin rates, which translated into fewer local 
recurrences. This has spurred a debate about whether RT remains necessary in the 
patient who has undergone an appropriate and successful TME. This question was 
addressed in the TME trial set up by the Dutch Colorectal Cancer Group that 
randomized between standardized and quality-controlled TME surgery alone and TME 
surgery preceded by short-term preoperative RT.17  This study helped clarify the 
contribution of neoadjuvant radiation to rectal cancer therapy and underscored the 
importance of proper surgical technique.  First, the authors demonstrated that 
neoadjuvant radiation does not influence long-term survival.  Second, they confirmed 
that neoadjuvant radiation improves local control even after TME is performed.  Third, 
the rate of local recurrence for patients treated without RT was substantially lower than 
the 25% local recurrence noted in the historical rectal cancer trials.  The Dutch study 
thus demonstrated that superior surgical technique is able to dramatically reduce local 
recurrence. 
 
In addition to surgical advances, significant advances have been made in systemic 
chemotherapy for patients with colorectal cancer.18-20  Response rates for patients with 
primary and metastatic colorectal cancer treated with modern chemotherapy regimens 
such as 5-FU, leucovorin, oxaliplatin (FOLFOX) have routinely exceeded 50% and are 
frequently as high as 60%-70%.19,20  In the context of improved surgical technique, 
improved chemotherapy, and better radiologic staging, many have questioned whether 
rectal cancer treatment can be streamlined and/or simplified. 
 
1.1.5  Neoadjuvant FOLFOX chemotherapy without radiation therapy as a 
potentially new option for locally advanced rectal cancer. 
This current protocol builds on work conducted by investigators at the Memorial Sloan-
Kettering Cancer Center.  In a single-institution trial (MSKCC07-021) that started in 
March 2007, 32 rectal cancer patients were treated with neoadjuvant FOLFOX 
chemotherapy instead of standard whole pelvic chemoradiation over 5.5 weeks.  
Patients also received bevacizumab for the first 4 cycles of therapy.  Two patients did 


 
 
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not complete neoadjuvant FOLFOX secondary to cardiac complications likely 
attributable to bevacizumab.  Of the 30 who did complete neoadjuvant treatment, all had 
R0 resections including TME.  Eight of those 30 had pathologic complete responses 
(pCR) (27%). One patient died postoperatively, and 3 patients experienced a 
recurrence. All 3 recurrent patients had distant metastasis to the lung. With a mean 
follow–up of 27 months no study participant had a pelvic recurrence, which is notable 
since none received pelvic RT.  These results were so striking that they have led to an 
ongoing National Cancer Institute-sponsored phase II/III clinical trial (NCT01515787) 
evaluating the use of neoadjuvant chemotherapy alone in locally advanced rectal 
cancer patients who are planned to undergo a low anterior resection with total 
mesorectal excision.  The phase II component of the trial aims to assure that 
neoadjuvant FOLFOX maintains a high rate of pelvic R0 resection compared to 
standard pelvic chemoradiation and is also non-inferior with respect to time to local 
recurrence.  The phase III component of the trial aims to compare the pCR rate 
between neoadjuvant FOLFOX and standard pelvic chemoradiation.  Lastly, this trial 
also will evaluate treatment-related toxicity from each of the respective treatment arms.   
 
1.2 Rationale for using whole pelvic low dose fractionated radiation therapy 
(LDFRT) for locally advanced rectal cancer patients. 
Gastrointestinal carcinomas are known to be radiosensitive, which has resulted in 
extensive use of RT for rectal cancer. As previously discussed, while standard whole 
pelvic RT is highly effective in decreasing the probability of pelvic recurrence for rectal 
cancer patients a significant drawback of using standard RT doses includes potentially 
serious RT-related morbidity.  The likelihood of serious acute and late RT-related 
morbidity is well known to correlate with the total RT dose prescribed as well as the 
dose delivered per fraction.  Because locally advanced rectal cancer patients may 
harbor occult metastatic disease outside of the pelvis neoadjuvant full dose 
chemotherapy (i.e. FOLFOX) should be combined with concurrent standard pelvic RT 
prior to reap the benefits of optimal systemic and locoregional treatment.  However, this 
is not done in practice because the cumulative toxicity would be unacceptably high.  
Thus, an optimal combination of chemotherapy and pelvic RT is needed to address both 
potentially distant occult metastatic disease and gross pelvic disease, respectively.  
 
Traditional thoughts in radiation biology of tumors suggested that doses of at least 120 
cGy were required to overcome the initial shoulder of the cell survival curve.  In practice, 
the standard dose per fraction is considered to be 150-220 cGy per fraction although 
the vast majority of patients are treated with either 180 cGy or 200 cGy fractions.  
Laboratory and clinical data suggest that a new paradigm using LDFRT as a 
chemopotentiator may allow full-dose drug therapy with improved efficacy without 
adding to the toxicity of the systemic treatment.21-26 This chemopotentiating effect is 
possible through a phenomenon known as hyper-radiation sensitivity (HRS) by which 
there is more effective tumor cell killing than would be predicted when using doses per 
fraction below 100 cGy.  This is followed by a change in slope of the survival response 
with increasing doses per fraction, indicating increased radioresistance (IRR) (Figure 1). 
This phenomenon was first described by Joiner and colleagues in the Gray Laboratory 
in 1986 and has since been well described by a number of laboratories.27  It also has 


 
 
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been documented in the clinical setting; in a study by Harney et al. patients with paired 
cutaneous metastases from sarcoma and melanoma had longer time to tumor regrowth 
after LDFRT than with conventional radiation.26  In vitro studies have established a link 
between (HRS/IRR) and evasion of the early G2/M cell cycle checkpoint.21,28,29  
Exaggerated HRS/IRR responses were found for enriched populations of G2-phase 
cells in one study, indicating that the mechanism likely involved events in the G2-phase 
of the cell cycle.  Two G2 checkpoints have been described, and the more recently 
discovered “early” checkpoint is rapidly activated after radiation exposure.  It is believed 
to prevent cell cycle progression through G2 of cells with unrepaired radiation-induced 
DNA damage.  The signaling cascade regulating the early G2/M checkpoint is initiated 
through ataxia telangiectasia mutated (ATM) activity.  Joiner and colleagues have 
shown that inhibition of ChK1 and Chk2, two proteins integral to the G2/M transition, 
can influence the cell-cycle response to low-dose radiation.28  It is believed that failure 
of the cell to repair DNA damage in G2-phase cells leads to increased apoptosis.  
Nonetheless, inhibition of ChK1 and ChK2 also lead to IRR at radiation doses > 0.2 Gy.  
This is consistent with reports indicating that low dose radiation can stimulate repair of 
DNA damage.  Interestingly, low dose radiation can also stimulate antioxidant capacity, 
apoptosis, and induction of immune responses, which collectively may provide effective 
local tumor control.30  In addition, hypoxia and nitric oxide levels can also affect cells 
sensitivity to radiation.  Reduction of nitric oxide level enhances the radiosensitivity of 
hypoxic non-small cell lung cancer.  Therefore, the identification of cellular pathways 
that are responsive to low-dose radiation and their contribution to chemopotentiation is 
highly significant because this will provide a better measurement of the therapeutic 
response and contribute to the rational design of mechanism-based clinical trials. 
 
Figure 1.  Induced Repair Model of 
Cell Survival.  Shown are the 
parameters of the “induced repair” (IR) 
model of cell survival, which provides a 
statistically better fit in the low dose 
region than the linear quadratic model in 
cell lines exhibiting hyperradiosensitivity 
(HRS).  The presence of HRS is 
supported by αs/αr ≠ 1 and dc ≠ 0 Gy.  
For the Joiner data in Figure 1, αs/αr = 
13.6 and dc = 0.21Gy.  The best-fit 
parameters of the “induced-repair” or the 
linear-quadratic (LQ) model were 
obtained using JPM® SAS software 
(Cary, NC), also used to analyze our 
data.  This data is unpublished. 
 
 
1.2.1  Preclinical HRS data for colorectal cancer cells. 
Preclinical data demonstrates increased radiation sensitivity in a variety of tumor cell 
lines including colorectal cells.31-35  Investigators at the University of Kentucky have 
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p53 status.34  Colony-forming assays were performed in HCT-116 (wild-type p53) and 
HT-29 (mutant p53) colorectal cell lines after exposure to LDFRT 50-60 cGy, paclitaxel 
1-10 nanomolar (nM), or LDFRT and paclitaxel.  LDFRT and paclitaxel given 
concurrently showed enhanced radiosensitization among the HCT-116 cells (surviving 
fraction (SF)(2)=0.138; D(0)=103 cGy) although not in HT-29 cells (SF(2)=0.608; 
D(0)=306 cGy).  However, both HCT-116 and HT-29 cells had increased radiosensitivity 
when 50 or 100 cGy fractions were given to a total of 200 cGy after pretreatment with 
paclitaxel.   
 
Unpublished preclinical data from the University of Maryland Medical Center also 
support that a HRS phenomenon occurs in colorectal cells in response to LDFRT.  
Colorectal carcinoma RKO and HCT-116 cells were plated at 200 cells per well in p6 
well plates in triplicate. Plating efficiency were 53 and 43 % respectively. The cells were 
irradiated twice daily 4.5 hours apart for 2 days.  The dose per fraction ranged from 0.05 
Gy up to 2 Gy, as shown in Figure 2.  On the first day of radiation the cells were 
exposed to 5-FU 1.15 millimolar (mM), oxaliplatin 0.18 mM and leucovorin 2mM. On day 
two of irradiation the cells were exposed to 5-FU 1.15 mM.  The chemotherapy doses 
were adjusted to produce 50% survival in a cell based assay.  Cells were allowed to 
grow for 7-10 days following initial treatment after which the colonies (≥ 50 cells) were 
fixed, stained and counted. Relative survival is expressed as a percentage of surviving 
colonies in reference to the mean plating efficiency of three sham-irradiated control 
plates.  Chemotherapy enhancement ratio (ER) by radiation was calculated using the 
following formula based on surviving fraction (SF): mDCF ER = SFmDCF alone/ SFmDCF + 
radiation. Ratio above 1 indicate enhancement.  There was clear chemopotentiation from 
LDFRT in the RKO cell line.  The HCT-116 cell line showed potentiation at 0.25 Gy. 
 
Figure 2.  A-B) Clonogenic survival assays performed on RKO and HCT-116 colorectal 
cancer cell lines.  Relative survival is expressed as a percentage of untreated cells.  C-
D) Chemotherapy enhancement ratio (ER) by radiation was calculated using the 
following formula based on surviving fraction (SF): mDCF ER = SFmDCF alone/ SFmDCF + 
radiation 


 
 
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1.2.2  Clinical experience with LDFRT. 
Based on promising preclinical data, clinical studies have been performed in a variety of 
cancer types with LDFRT in addition to standard chemotherapy. Investigators at the 
University of Kentucky published their experience using carboplatin and paclitaxel with 4 
fractions of 80 cGy each in locally advanced head and neck cancer patients.25 They 
observed toxicities similar to those expected from chemotherapy alone and concluded 
that the addition of LDFRT was “extremely well tolerated.” Moreover, they reported 
excellent response rates. Regine et al. conducted a phase I trial of low-dose abdominal 
RT (60 vs. 70 cGy fractions, total 8 fractions) and gemcitabine 1,250 mg/m2 among 
patients with unresectable pancreatic/small bowel carcinomas.36 The authors concluded 
that abdominal LDFRT using 60-cGy fractions was well tolerated when given 
concurrently with full-dose gemcitabine. A multi-institutional phase II trial using this 
regimen suggested improved efficacy of the combined regimen in improving overall 
survival. Sixty-one percent of enrolled patients experienced at least stable disease, and 
median survival in this poor prognosis population was 13 months. More important, no 
additional toxicity was observed with the low-dose radiation other than that expected 
from the high dose of gemcitabine. More recently, Wrenn et al. published results of a 
phase I study of low-dose whole-abdominal RT and full-dose cisplatin in optimally 
debulked stage III/IV endometrial cancer patients.37 Because treatment was well 
RKO
0
20
40
60
80
100
0
0.5
1
1.5
2
Radiation doses (GY)
Relative Survival (%)
XR
XR+Drug
* 
* 
* 
* 
HCT116
0
20
40
60
80
100
0
0.5
1
1.5
2
Radiation doses (GY)
Relative Survival (%)
XR
XR+Drug
Dose Gy 
FOLFOX ER 
0 
1 
0.05 
0.92 
0.1 
1.02 
0.15 
0.97 
0.25 
1.38 
0.5 
0.93 
1 
1.32 
2 
0 
Dose Gy 
FOLFOX ER 
0 
1 
0.05 
1.06 
0.1 
0.95 
0.15 
1.57 
0.25 
1.88 
0.5 
2.09 
1 
5.6 
2 
0 
A. 
B. 
C. 
D. 
Fig. 2 


 
 
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tolerated, the authors concluded that further investigation was warranted to determine 
treatment efficacy.    
 
1.2.3 Experience with using bone marrow–sparing intensity-modulated radiation 
therapy (IMRT).  
In addition to our experience using LDFRT, we have also successfully used IMRT to 
spare bone marrow based on the phase II study reported by Rochet and coworkers.38 
By utilizing this approach, we have been able to safely deliver significantly higher doses 
of whole-abdominal RT similar to that proposed in this protocol; patients treated in this 
fashion have not required treatment breaks because of hematologic toxicity. Moreover, 
a bone marrow–sparing approach is prudent given our strategy of using concurrent 
FOLFOX, which causes more hematologic toxicity than 5-FU alone.   
 
1.3  Proposed study overview. 
The current standard of care for treatment of locally advanced rectal cancer consists of 
neoadjuvant whole pelvic RT with radiosensitizing single-agent 5-FU followed by 
surgery and adjuvant full dose chemotherapy (typically FOLFOX).  For all clinical T3, 
T4, and/or lymph node positive rectal cancer patients the standard neoadjuvant 
radiation dose per fraction is 180 cGy delivered on consecutive weekdays over 5.5 
weeks for a total of 5040 cGy.  A potentially paradigm-changing approach is currently 
being investigated in a phase II/III trial in which neoadjuvant RT is omitting in favor of 
using full dose FOLFOX chemotherapy based on provocative data published from 
Memorial Sloan Kettering Cancer Center.  We hypothesize that whole pelvic LDFRT 
using 40 cGy fractions for a total of 960 cGy can be safely added concurrently to 
neoadjuvant full dose FOLFOX as an alternative to standard neoadjuvant 5-FU 
chemoradiation.  We further hypothesize that using LDFRT as a chemopotentiatior will 
significantly increase the pCR rate as reported by the Memorial Sloan Kettering pilot 
study of 27%.  Lastly, due to the significantly lower radiation dose per fraction and lower 
total radiation dose we expect that this novel strategy will not cause higher rates of 
severe toxicity compared to neoadjuvant FOLFOX alone. 
 
Specifically, this phase II trial intends to determine whether 6 cycles of neoadjuvant 
FOLFOX with concurrent LDFRT followed by comprehensive restaging and TME 
achieves favorable outcomes for patients with T3N0M0, T3N1M0, or T2N1M0 rectal 
cancer. As mentioned above, the current standard of care for all locally advanced rectal 
cancer patients includes radiosensitizing 5-FU and concurrent whole pelvic RT to 5040 
Gy in 180 Gy once daily fractions.  Per the proposed protocol, T3N0M0, T3N1M0, or 
T2N1M0 rectal cancer patients who are eligible to undergo a low anterior resection 
would receive whole pelvic RT to 960 cGy in 40 cGy fractions delivered twice daily on 
days 1-2 of each cycle of FOLFOX chemotherapy for a total of 6 cycles.   
 
Eligible study subjects include adults who are candidates for curative intent sphincter-
sparing surgery and who lack high-risk features, particularly tumor encroaching upon 
the mesorectal fascia (within 3 mm) as determined by pre-treatment endoscopic 
ultrasound (EUS) and/or magnetic resonance imaging (MRI) or distal rectal tumors (<5 
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This study has the potential to dramatically influence our approach to treating rectal 
cancer by improving on the single-institution experience reported by Schrag and 
coworkers at Memorial Sloan–Kettering.  Based on the previously reported ability of 
LDFRT as a chemopotentiator to improve treatment outcomes with no significant 
increase in toxicity as seen in other disease sites, we anticipate that the addition of 
LDFRT to neoadjuvant chemotherapy will augment the encouraging data published 
from Memorial Sloan–Kettering.   
 
2.0  OBJECTIVES 
 
2.1  Primary Objective 
To determine whether the addition of concurrent LDFRT to neoadjuvant full dose 
FOLFOX results in a pCR response rate of at least 35%. 
 
2.2  Secondary Objective 
To assure that neoadjuvant concurrent LDFRT-FOLFOX maintains a high rate of pelvic 
R0 resection compared to standard preoperative chemoradiation and total mesorectal 
excision surgery. 
 
3.0  ELIGIBILITY 
 
3.1  Inclusion Criteria 
3.1.1 ≥ 18 years old at diagnosis. 
3.1.2 ECOG Performance Status 0, 1, or 2. 
3.1.3 Biopsy-proven diagnosis of rectal adenocarcinoma. 
3.1.4 Clinical AJCC 7th edition stage T2N1M0, T3N0M0 or T3N1M0 based on physical 
examination, CT scan chest or chest x-ray AND CT abdomen or MRI abdomen 
AND pelvic MRI or endorectal ultrasound (ERUS). 
3.1.5 Preoperative lower gastrointestinal endoscopy (proctoscopy, sigmoidoscopy, 
colonoscopy) confirming tumor extent as no less than 5 cm and no greater than 12 
cm from the anal canal. If endoscopy is not rigid, CT or MRI can be used to 
indicate location from anal canal. 
3.1.6 Evaluation by a surgical oncologist, radiation oncologist, and medical oncologist 
≤ 28 days prior to registration. 
3.1.7 Confirmation that the patient is able to undergo a low anterior, sphincter-sparing 
resection with total mesorectal excision ≤ 28 days prior to registration. 
3.1.8 In the absence of treatment on a clinical trial, the patient would be recommended to 
receive neoadjuvant chemoradiation followed by curative intent surgery. 
3.1.9 The following laboratory values obtained ≤ 14 days prior to registration: 
 Absolute neutrophil count (ANC) ≥ 1500/mm3. 
 Platelet count ≥ 100,000/mm3. 
 Hemoglobin > 8.0 g/dL.  May transfuse to meet eligibility. 
 Total bilirubin ≤ 1.5 x upper limit of normal (ULN). 
 SGOT (AST) ≤ 3 x ULN. 
 SGPT (ALT) ≤ 3 x ULN. 


 
 
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 Creatinine ≤ 1.5 x ULN. 
3.1.10 Baseline CEA within 14 days of registration 
3.1.11 
Negative serum pregnancy test (B-HCG) within 14 days prior to registration 
for women of childbearing potential. 
3.1.12 
Did the patient provide study-specific informed consent prior to study entry? 
3.1.13 
Willingness to return to the enrolling medical site for all study assessments. 
 
3.2 Exclusion Criteria 
3.2.1 Clinical T4 tumor. 
3.2.2 Surgeon indicates the need for an abdominal perineal resection (APR) at 
baseline. 
3.2.3 Previous pelvic RT. 
3.2.4 Autoimmune disease such as scleroderma, lupus, or inflammatory bowel 
disease. 
3.2.5 Tumor < 3 mm from the mesorectal fascia as seen on MRI or endorectal 
ultrasound. 
3.2.6 Tumor-induced symptomatic bowel obstruction. 
3.2.7 Chemotherapy (including hormonal therapy) within the past 5 years from date of 
registration. 
3.2.8 Other invasive malignancies within past 5 years from date of registration. 
3.2.9 Pregnant or nursing women. 
3.2.10 Men or women of childbearing potential who are unwilling to employ adequate 
contraception. 
3.2.11 Other co-morbid conditions that, based on the judgment of the physicians 
obtaining informed consent, would make the patient inappropriate for this study. 
3.2.12 Any conditions that would preclude a patient from completing all study 
assessments. 
 
4.0  REGISTRATION 
Patients can be registered only after all eligibility criteria are met.  The date of 
registration/enrollment is considered to be the day the Eligibility Checklist is signed by 
the verifying physician.  Once a patient is enrolled, a unique case number will be 
assigned to the patient in ONCORE. 
 
5.0  TREATMENT PLAN 
Treatment must begin within 14 days of registration.  
 
5.1  Chemotherapy 
Neoadjuvant FOLFOX (5-FU + leucovorin + oxaliplatin) 
This regimen will be repeated every 2 weeks for 6 cycles; (1 cycle = 14 days). 
 
Given first:  Oxaliplatin 85 mg/m2 IV in D5W 500 mL over 2 hours, Day 1 
Given second:  Leucovorin 200 mg/m2 IV bolus in D5W 250 mL over 2 hours, Day 1 
Given third:  5-FU 400 mg/m2 IV bolus in a syringe given over 5–15 minutes, Day 1, 
then 2,400 mg/m2 in 240 mL of 0.9% Sodium Chloride via continuous IV infusion over 
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Note:  Oxaliplatin is administered first, prior to leucovorin; alternatively leucovorin may 
be administered (via separate infusion containers) concurrently with oxaliplatin. 
 
5.1.1 If necessary to accommodate holidays, patient schedule or other justified 
circumstance approved by the PI, the schedule may be modified by ± 3 days. 
 
5.1.2 Chemotherapy dose modification is at the discretion of the treating medical 
oncologist, although any patient who requires dose modification below dose level -2 
will be removed from study participation.  There are no restrictions on dose 
modifications for the sixth cycle of FOLFOX. 
 
5.1.3 Patients who cannot tolerate 6 cycles of FOLFOX or those who require dose 
modification below dose level -2 or those who are found to be ineligible for the study 
based on central review of either the baseline or the follow up MRI or those that 
withdraw consent will receive preoperative combined modality chemoradiation with 
infusional 5-FU.  There are no restrictions on dose modifications for the 6th cycle of 
neoadjuvant FOLFOX.   
 
5.1.4 Patients receiving oxaliplatin on this study should be counseled to avoid cold 
drinks, chewing ice chips, and exposure to cold water or air because the sensory 
neurotoxicity often seen with oxaliplatin appears to be exacerbated by exposure to 
cold.  The period of time during which the patient appears to be at risk for these 
cold-induced sensory neuropathies is not well documented.  Patients should 
exercise caution regarding cold exposure during the treatment period.  Peripheral 
sensory neuropathies can occur at any time after receiving oxaliplatin therapy. 
 
5.1.5 Concurrent medications are at the discretion of the treating physician. 
 
 
Current Greenebaum Comprehensive Cancer Center recommended:  
 
 
Ondansetron 16 mg PO daily, if patient unable to take orally give 8 mg IV. 
 
 
Dexamethasone 12 mg PO daily, if; unable to take orally give IV. 
 
5.1.6 Adjuvant chemotherapy is at the discretion of the treating physician and is not 
considered part of protocol therapy. 
 
5.2  Radiation therapy 
 
5.2.1 Simulation:  Will be performed prior to initiation of therapy with patients in the 
supine position and arms above the head.  One Vac-Lock bag will be used for 
positioning and immobilization placed at the level of the pelvis.  No oral or IV 
contrast is required.  CT simulation from the cranial extent of L1 to the level of the 
lesser trochanter will be performed to ensure adequate coverage and dosimetric 
parameters. 
 
5.2.2 Volumes:  The gross tumor volume (GTV) should be contoured using all 
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The clinical target volume (CTV) should include the GTV as well as elective lymph 
node regions (internal iliac, mesorectal, presacral).  Since patients with low lying 
rectal tumors and T4 rectal tumors will not be included in this study, the external iliac 
and inguinal lymph nodes should not be included as they are not felt to be at a 
significant clinical risk of subclinical involvement.  A planning target volume (PTV) 
should be created using a 0.5 cm uniform expansion from the CTV to account for 
daily set up variability provided daily kilovoltage (kV) imaging is used for image 
guidance.  If daily kV imaging is not available, then larger PTV margins should be 
used based on the discretion of the treating physician.  Normal structures to be 
contoured include small bowel (up to 1 cm superior to PTV), bladder, femoral heads, 
and pelvic bones (including the sacrum, ilium, ischium, and pubic bones as a 
surrogate for bone marrow). 
 
5.2.3 Technique:  To limit dose to bone marrow, LDFRT will be delivered using 
intensity modulated radiation therapy (IMRT).  IMRT may be delivered using either 
static beams or volumetric-modulated arc therapy (VMAT).  Since the total 
prescribed radiation dose used in this study is well below the established tolerance 
levels of all normal tissues that will be contoured, no specific normal dose 
constraints should be used.  However, a priority should be made to limit the volume 
of the pelvic bones (as a surrogate for bone marrow) receiving the prescription dose. 
 
5.2.4 Dose: 40 cGy fractions will be administered twice daily on Days 1 and 2 of 
each cycle of FOLFOX with each radiation fraction being delivered a minimum of 4 
hours apart.  This will be repeated every 2 weeks for a total dose of 960 cGy.   
 
5.2.5 Treatment Planning Objectives: 
100% of the PTV should be covered by at least 95% of the prescription dose. 100% 
of the CTV should be covered by at least 95% of the prescription dose. No greater 
than 110% of the prescription dose should be delivered to no greater than 0.03 cc of 
the PTV.  
 
6.0  RESTAGING 
Restaging will take place 4 weeks (±1 week) after completion of 6 cycles of FOLFOX 
and LDFRT. The patient will see the physician and have labs and imaging completed 
per Appendix I scheduling. Repeat imaging should include the same modality used at 
baseline. For example, if a baseline MRI was performed, a post-LDFRT-FOLFOX MRI 
should be repeated. If a baseline endorectal ultrasound (ERUS) was performed, a post-
LDFRT-FOLFOX ERUS and CT scan should be repeated.  
 
The decision to proceed to TME directly, or alternatively receive standard 
chemoradiation off protocol followed by TME, will be based on radiological and clinical 
tumor response. 
 
Patients will proceed directly to TME unless any of the following occurs, at which time 
they will be discontinued from treatment on this study and be recommended to pursue 
appropriate treatment off-study.   


 
 
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 If there is any evidence of progressive disease (PD) by either imaging or 
clinical assessment. 
 If a patient with radiologically measurable disease has an overall 
radiologic tumor response status of stable disease (SD). 
 If a patient with disease that is not radiologically measurable has a clinical 
tumor response of 20% or less as determined by endoscopy. 
 
6.1 Radiological tumor evaluation 
Assessment will be according to the revised Response Evaluation Criteria in Solid 
Tumors (RECIST) guidelines, version 1.39 
 
6.1.1 Timing of restaging evaluation: Patients should undergo re-evaluation 4 
weeks (± 1 week) after the completion of 6 cycles of FOLFOX and LDFRT. 
 
6.1.2 Definitions of measurable and non-measurable disease 
 
6.1.2.1 Measurable disease (standard definition per RECIST): 
 
 A non-nodal lesion is considered measurable if its longest diameter can 
be accurately measured as at least 2.0 cm with chest x-ray, or as at 
least 1 cm with CT scan, CT component of a PET/CT or MRI. 
 A superficial non-nodal lesion is measurable if its longest diameter is at 
least 1 cm in diameter as assessed using calipers or imaging. 
 A malignant lymph node (LN) is considered measurable if its short axis 
is at least 1 cm when assessed by CT scan or pelvic MRI 
 
6.1.2.2 Non-measurable disease (standard definition per RECIST): 
 
 All other lesions or sites of disease are considered non-measurable 
disease, including pathological nodes (those with a short axis at least 1 
cm to less than 1.5 cm.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory 
breast disease, and abdominal masses (not followed by CT or MRI) or 
considered non-measurable as well. 
 
6.1.3 Guidelines for evaluation of measurable disease 
 
6.1.3.1 Measurement methods 
 
 
All measurements should be recorded in metric notation (i.e. decimal 
fractions of centimeters) using a ruler or calipers. 
 
The same technique and method of assessment must be used at 
baseline and during follow-up. 
 
6.1.3.2 Acceptable modalities for measurable disease 
 


 
 
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 Conventional CT and MRI: This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 
5 mm or less. If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness. 
 For this study, when an MRI is performed, the technical specifications of 
the scanning sequences used should be optimized for the evaluation of 
the type and site of disease. The lesions should be measured on the 
same pulse sequence. Ideally, the same type of scanner should be 
used and the image acquisition protocol should be followed as closely 
as possible to prior scans. Body scans should be performed with breath-
hold scanning techniques, if possible. 
 PET-CT: The CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT 
in accurately measuring cancer lesions over time. 
 Evaluation of disease by MRI is preferred. However, for patients who 
are not able to undergo an MRI or for clinicians who prefer it, an ERUS 
is acceptable. If ERUS is performed as an alternative to MRI at 
baseline, then an ERUS must also be performed at the time of 
restaging. 
 In cases where ERUS is the modality selected to evaluate the primary 
rectal tumor, an accompanying CT for complete pelvic disease staging 
will also be interpreted by the on-site radiologist. 
 A standard CT of the abdomen and pelvis or chest, abdomen and pelvis 
with oral and intravenous contrast is required. In the event that 
radiologic studies yield inconsistent interpretation of T stage or N stage 
the modality that assigns the highest T stage or the highest N stage 
should be used for purposes of protocol eligibility. 
 
6.1.4  Measurement of effect – imaging response to neoadjuvant LDFRT-
FOLFOX 
 
“Adapted RECIST” as defined in this protocol consists of the following: 
6.1.4.1 Target Lesions & Target Lymph Nodes 
 The Rectal Primary tumor is the primary target lesion. In addition, 
associated pelvic lymph nodes should be recorded and measured at 
baseline. 
 The primary rectal lesion is measured and followed as a bi-dimensional 
product to avoid measurements that include the GI tract lumen whether 
collapsed or filled with air, feces or contrast material that does not 
represent tumor tissue. The Bi-Dimensional Product (BDP) is the 
product of the longest diameter for the rectal primary tumor and the 
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any objective tumor response in the measurable dimension of the 
disease. 
 Post-Baseline Bi-Dimensional Product (PBDP): The product of the 
longest diameter of the rectal primary tumor multiplied by the thickest 
wall will be calculated and reported as the post-bi-dimensional product 
(PBDP). If the radiologist is able to provide an actual measure for the 
target even if it is below 0.5 cm. If the target is believed to be present 
and is faintly seen but too small to measure, a default value of 0.5 cm 
should be assigned. If it is the opinion of the radiologist that the rectal 
primary has likely disappeared, the measurement should be recorded 
as 0 cm. 
 Given increased error in measuring smaller structures, and given 
differing qualities of MRI and their resolution, diminutive nodes are 
those measuring 0-0.4 cm. These will not be considered evaluable for 
change. Evaluable nodes are those 0.5 cm or greater in the mesorectal 
and superior hemorrhoidal location. 
 To be labeled as a target lymph node: up to 4 nodes in the mesorectal, 
superior hemorrhoidal and internal iliac regions may be considered 
“target” lymph nodes if they measure 0.5 cm or greater in short axis. 
 To categorize the primary tumor as consistent with clinical stage N2 
disease, ≥4 lymph nodes must measure >1 cm in short axis. 
6.1.4.2 Imaging Response Criteria 
6.1.4.2.1 All target lesions and target lymph nodes followed by imaging 
and physical examination must be measured on reevaluation 
at evaluation times specified in Section 6.1. Specifically, a 
change in objective status to either a PR or CR cannot be 
made without re-measuring target lesions and target lymph 
nodes. 
 
6.1.4.2.2 For purpose of restaging, a target lymph node must measure 
0.5 cm or more in short axis. 
 
 Target lymph nodes, which at baseline measure between 0.5 
and 1 cm short axis inclusive, must increase 0.3 cm in size to 
be considered PD. Nodes between 1.1 and 2 cm short axis 
inclusive must increase in size 0.4 cm to be considered PD. 
Nodes 0.2 cm and greater in short axis must increase in size 
by 25%, (e.g., 0.2 cm to 2.5 cm, or 2.5 cm to 3.1 cm) to be 
considered PD. 
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1 cm in short axis diameter to be considered evaluable and 
will follow same rules as above for absolute increase in size. 
 Complete LN response requires radiological disappearance 
of initially abnormal lymph nodes or maintenance of 1.9 cm or 
less size of LN from this baseline “normal” definition. 
6.1.4.2.3 Evaluation of the Rectal Primary and Target Lymph Nodes. 
 
1. Complete 
Response (CR) 
All of the following must be true: 
a. Disappearance of the rectal primary. 
b. Each target lymph node must have 
decreased short axis to <0.5 cm. 
c. No new sites of disease. 
2. Partial Response 
(PR): 
At least a 20% decrease in PBDP (bi-
dimensional product of primary rectal lesion) 
taking as reference the BDP.  No new sites of 
disease. And no PD of any target lymph 
nodes. 
3. Stable disease 
(SD) 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD. 
4. Progression (PD) 
At least one of the following must be true: 
At least one new malignant lesion, which also 
includes any LN that was normal at baseline (< 
0.5 cm short axis) and increased to ≥ 0.5 cm 
short axis during follow-up. 
At least a 20% increase in PBDP (bi-
dimensional product of rectal primary lesion). 
 
 
 
 
6.1.4.3 Overall radiologic tumor response status after neoadjuvant LDFRT-
FOX 
The radiologic response status after neoadjuvant LDFRT-FOLFOX is 
determined by combining the patient’s status including primary rectal 
tumor, target lymph nodes, and new disease as defined below: 


 
 
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Primary Rectal 
Tumor & Target 
Lymph Nodes 
New Sites of 
Disease 
Overall 
Radiographic Tumor 
Response Status 
CR 
No 
CR 
PR 
No 
PR 
SD 
No 
SD 
Not all evaluated 
No 
Not evaluated 
PD 
Yes or No 
PD 
 
6.2  Clinical tumor evaluation 
Baseline and re-evaluation proctoscopy should be performed by the surgeon.  The 
surgeon should perform pre and post treatment examinations.  A gastroenterologist 
may perform proctoscopy in lieu of the surgeon, but then must also perform the follow-
up examination.  Proctoscopy includes colonoscopy, flexible sigmoidoscopy as well as 
rigid proctoscopy. 
 
Follow-up proctoscopy should be performed within 3-5 weeks after the completion of 
LDFRT-FOLFOX. 
 
6.2.1 Guidelines for evaluation of clinically evaluable disease 
 
6.2.1.1 Definition of clinically evaluable disease 
 
To be clinically evaluable, a tumor must be directly visualized at proctoscopy 
and estimated to have a clinical bidimensional product (BDP) of ≥ 1 cm. 
 
6.2.1.2 Clinical tumor response based on proctoscopy can be classified as the 
following: 
 
 Complete response (100%) 
 Major response (51-100% smaller) 
 Moderate response (21-50% smaller) 
 Minimal response (0-20% smaller) 
 Progression (tumor enlargement) 
 Unable to determine 
 
6.2.1.3 Treatment decision after re-evaluation following LDFRT-FOLFOX 
 
 If there is evidence of progressive disease on imaging or clinical 
assessment, the patient should be referred for standard neoadjuvant 
chemoradiation off protocol followed by TME. 
 If a patient with radiologically measurable disease has an overall imaging 
tumor response status of stable disease, the patient should be referred for 
standard neoadjuvant chemoradiation off protocol followed by TME. 


 
 
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 If a patient with disease that is not radiologically measurable has a 
minimal clinical tumor response, the patient should be referred for 
standard neoadjuvant chemoradiation off protocol followed by TME. 
 Otherwise, the patient should proceed directly to TME. 
 
7.0  SURGERY 
Following restaging, patients without evidence of progressive disease, stable disease, 
or clinical tumor response of 20% or less will undergo a total mesorectal excision (TME) 
to be performed about 6-8 weeks after completion of LDFRT-FOLFOX. Total mesorectal 
excision is performed off study as part of standard of care.  
 
Follow up visits will be off protocol and scheduled as per standard of care. Patients will 
be followed only for survival. 
 
8.0  PATHOLOGICAL TUMOR ASSESSMENT 
 
8.1 Definition of surgical margin status 
 
8.1.1 Margin type 
 Proximal: most cephalad portion of the specimen 
 Distal: most caudad portion 
 Radial: outer circumference of the specimen 
 
8.1.2 Margin positivity 
 Positive: tumor ≤ 1 mm from any edge of the primary tumor specimen 
 Close: tumor >1 but ≤ 3 mm from any edge of the primary tumor specimen 
 Negative: no tumor within 3 mm from any edge of the primary tumor specimen 
 
8.2 Degree of pathologic treatment response 
 
8.2.1 Pathological complete response (pCR) 
 
A pCR indicates that no gross or microscopic tumor is identified anywhere 
within the primary tumor specimen or any lymph nodes. 
 
8.2.2 Pathologic response other than a pCR 
 
The definition of a non-pCR will include any surgical specimen that has any 
evidence of residual tumor manifest in the primary or regional lymph nodes. 
 
For patients who do not meet criteria for a pCR, the extent of response to pre-
operative therapy will be graded using the Tumor Regression Grade (TRG) 
schema that is included in the AJCC 7th edition. This was also used by Rodel 
in the pre/postoperative rectal cancer study and was subsequently adopted by 
the AJCC [Rodel (JCO 2005; 23:8688-8696)]. This schema evaluates the 


 
 
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degree to which the primary rectal tumor specimen has responded to 
neoadjuvant treatment. 
 
Tumor regression 
grade (TRG) 
Response 
categorization 
Description 
TRG 0 
Complete 
No viable cancer cells 
TRG 1 
Moderate 
Single cells or small 
groups of cancer cells 
TRG 2 
Minimal 
Residual cancer 
outgrown by fibrosis 
TRG 3 
Poor 
Minimal or no tumor kill; 
extensive residual cancer 
 
9.0  ADJUVANT THERAPY 
Adjuvant therapy will be prescribed at the discretion of the treating physician(s).  
Although not required by this protocol, patients with close or positive margins or other 
features felt by the treating physician(s) to be high risk factors for locoregional 
recurrence are recommended to receive standard adjuvant chemoradiation. 
 
10.0  DATA SAFETY MONITORING AND ADVERSE EVENT (AE) MONITORING 
AND REPORTING 
 
10.1 Data and Safety Monitoring / Quality Assurance Committee 
This study will be governed by the UMGCC Data Safety Monitoring / Quality Assurance 
Committee (DSMQAC).  The study will be sent to the DSMQAC for a mandatory interim 
review after the first 6 patients have been accrued.  Once the DSMQAC has reviewed 
and approved the initial 6 patients on the study, 24 additional patients will be enrolled.  
The study will be reviewed by the DSMQAC on an annual basis and a report will be 
uploaded in the continuing review submitted to the Institutional Review Board (IRB).  
 
On the basis of an optimal two-stage design to test the null hypothesis that P<=0.05 
(poor pCR response rate) versus the alternative that P>=0.25 (UMGCC DSMQAC 
committee feels that 25% response rate is a reasonable threshold) has an expected 
sample size of 16.76 and a probability of early termination of 0.63. If preoperative 
concurrent LDFRT and FOLFOX is actually not effective, there is a 0.05 probability of 
concluding that it is. If the treatment combination is actually effective, there is a 0.10 
probability of concluding that it is not.  After treating 9 patients in the first stage, the 
study will be terminated if 0 respond.  If the trial goes on to the second stage, a total of 
30 patients will be studied. If the total number responding is less than or equal to 3, the 
treatment combination will be rejected. 
 
10.2 Results Reporting on ClinicalTrials.gov 
At study activation, this study will be registered within the “ClincialTrials.gov” website.  
The Primary and Secondary Endpoints (i.e., “Outcome Measures”) along with other 
required information for this study will be reported on ClinicalTrials.gov.  For purposes 
of timing of the Results Reporting, the initial estimated completion date for the Primary 


 
 
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Endpoint of this study is 24 months after the study opens to accrual, including 15 months 
to accrual, about 9 months for the last patient enrolled to finish protocol treatment, and 
about 6 months for data cleaning and analysis.  The definition of “Primary Endpoint 
Completion Date” (PECD) for this study is at the time that all registered patient have 
been off treatment. 
 
10.3 Adverse Event Data 
This study is GCC investigator initiated and is not sponsor supported.  All adverse events 
will be reported via ONCORE. Serious unexpected adverse events will be reported to 
the UMB IRB via CICERO according to IRB guidelines. 
 
 Monitoring and scoring of adverse events will be performed as per the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 
All Adverse Events will be reported in ONCORE per DSMQAC. 
 
\\stccl1srv7\radonc\protocal\Protocol\DSMQAC 
 
https://oncoreweb1.umm.edu/login/ 
 The UMB IRB will be notified per UMB Human Research Protections Office 
(HRPO) guidelines.  
http://hrpo.umaryland.edu/includes/Study_Tool_Docs/Reportable-New-Information_6-28-11.pdf 
Serious Adverse Events that meet the University of Maryland Baltimore 
Institutional Review Board (UMB IRB) REPORTABLE NEW INFORMATION 
(RNI) will reported via https://cicero.umaryland.edu/ 
 
REPORTABLE NEW INFORMATION (University of Maryland, Baltimore 
Revision Date: 6/28/11) 
 
Report the information items that fall into one or more of the following 
categories to the IRB within 5 business days using this form: 
Information that does not fall under any of the categories does not require 
reporting to the IRB. 
1) Information that indicates a new or increased risk, or a safety issue. For 
example: 
a) New information (e.g., an interim analysis, safety monitoring report, publication 
in the literature, sponsor report, or investigator finding) indicates an increase in 
the frequency or magnitude of a previously known risk, or uncovers a new risk. 
b) An investigator brochure, package insert, or device labeling is revised to 
indicate an increase in the frequency or magnitude of a previously known risk, or 
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c) Withdrawal, restriction, or modification of a marketed approval of a drug, 
device, or biologic used in a research protocol 
d) Protocol violation that harmed subjects or others or that indicates subjects or 
others might be at increased risk of harm 
e) Complaint of a subject that indicates subjects or others might be at increased 
risk of harm or at risk of a new harm 
f) Any changes significantly affecting the conduct of the research 
2) Any harm experienced by a subject or other individual, which in the opinion of 
the investigator are unexpected and probably related to the research 
procedures. 
a) A harm is “unexpected” when its specificity or severity are inconsistent with 
risk information previously reviewed and approved by the IRB in terms of nature, 
severity, frequency, and characteristics of the study population. 
b) A harm is “probably related” to the research procedures” if in the opinion of 
the investigator, the research procedures more likely than not caused the harm. 
3) Non-compliance with the federal regulations governing human research or 
with the requirements or determinations of the IRB, or an allegation of such non-
compliance. 
4) Failure to follow the protocol due to the action or inaction of the investigator or 
research staff. 
5) Breach of confidentiality. 
6) Change to the protocol taken without prior IRB review to eliminate an apparent 
immediate hazard to a subject. 
7) Incarceration of a subject in a study not approved by the IRB to involve 
prisoners. 
8) Complaint of a subject that cannot be resolved by the research team. 
9) Premature suspension or termination of the research by the sponsor or the 
investigator. 
10) Unanticipated adverse device effect (any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a 
device, if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects.) 
11) Audit, inspection, or inquiry by a federal agency. 
12) Written reports of study monitors. 
13) For Veterans Administration (VA) research all local or internal unanticipated 
serious adverse events. (Note: VA is not a site for recruitment for this clinical 
trial.) 
 
 
10.5 Additional Instructions or Exclusions to Adverse Event Expedited Reporting 
Requirements for Commercial Agents in a non-IND trial 
 
• 
Treatment expected adverse events include those listed in the Informed Consent 


 
 
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Form (ICF) and in the package inserts for fluorouracil, leucovorin, and oxaliplatin. 
 
• 
Grade 3 or 4 myelosuppression and hospitalization resulting from such do not require 
expedited reporting via CICERO but will be reported in ONCORE and will be submitted 
as part of study results. 
 
• 
Other grade 1-4 events that are expected do not require expedited reporting via 
CICERO, even if they result in hospitalization. 
 
• 
Grade 4 events that are unexpected and that are at probably related (per UMB IRB 
definition) to treatment must be reported via CICERO within 5 calendar days per UMB 
IRB guidelines. 
 
• 
All new malignancies should be reported to the IRB whether or not they are thought 
to be related to either previous or current treatment. All new malignancies should be 
reported, i.e., solid tumors (including non-melanoma skin malignancies), hematologic 
malignancies, myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), 
and insitu tumors.  In CTCAE version 4.0, the new malignancies (both second and 
secondary) may be reported as one of the following: 
(1) Leukemia secondary to oncology chemotherapy,  
(2) Myelodysplastic syndrome,  
(3) Treatment-related secondary malignancy, or  
(4) Neoplasm other, malignant (grade 3 or 4).   
Whenever possible, the IRB reports for new malignancies should include, tumor 
pathology, history of prior tumors, prior treatment/current treatment including 
duration, any associated risk factors or evidence regarding how long the new 
malignancy may have been present, when and how the new malignancy was 
detected, molecular characterization or cytogenetics of the original tumor (if 
available) and of any new tumor, and new malignancy treatment and outcome, if 
available. 
 
• 
All pregnancies and suspected pregnancies occurring in female patients or in the 
partner of a male patient during therapy or within 28 days after completion of treatment 
on GCC 1314 must be reported to the IRB.  In CTCAE version 4.0, use the event 
term,“pregnancy, puerperium, and perinatal condition-other, fetal exposure (grade4)”. 
 
• 
IRB reports should be amended upon completion of the pregnancy to report 
pregnancy outcome (e.g. normal, spontaneous abortion, therapeutic abortion, fetal 
death, congenital abnormalities). 
 
• 
The IRB report should be amended for any neonatal deaths or complications 
occurring within 28 days of birth independent of attribution.  Infant deaths occurring after 
28 days considered to be related to in utero exposure to the agents used in this trial 
should be reported to the IRB. 
 
10.6 Assessment of Attribution 


 
 
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The following attribution categories are utilized when assessing whether an adverse 
event is related to a medical treatment or procedure: 
 
Definite – The adverse event is clearly related to the agent(s). 
Probable – The adverse event is likely related to the agent(s). 
Possible – The adverse event may be related to the agent(s). 
Unlikely – The adverse event is doubtfully related to the agent(s). 
Unrelated – The adverse event is clearly NOT related to the agent(s). 
 
11.0  DOSE MODIFICATION BASED ON ADVERSE EVENTS 
 
11.1  Radiation therapy 
Treatment interruptions are discouraged although may be necessary due to acute 
severe complications.  Documentation must be made for any such complications 
including the reason and length of the treatment interruption. 
 
If chemotherapy is held, then radiation therapy will be held.  If radiation is held, then 
chemotherapy would continue per physician discretion. 
 
Radiation therapy may be held for grade 4 cellulitis of the perineum or grade 4 
neutropenia or other radiation-associated toxicity.  Radiation should be restarted 
subsequent to recovery at the discretion of the treating radiation oncologist as per 
standard practice. 
 
Table 11.1  Radiation therapy modifications based on adverse events 
 
System/Organ/Class Adverse Event 
Dosage Change 
Blood/lymphatic 
system disorders 
Thrombocytopenia Grade 2 – Continue at current dose 
Grade 3 – Hold until recovery ≤ grade 
2 then resume 
Grade 4 – Hold until recovery ≤ grade 
2 (platelets ≥ 75 x 109/L) then resume 
Neutropenia 
Grade 3 or 4 – Hold until recovery ≤ 
grade 2 then resume 
Febrile 
Neutropenia 
Grade 3 or 4 – Hold until resolution of 
fever and neutropenia ≤ grade 2.  Hold 
until the ANC ≥ 1500/mm3 and fever 
has resolved then resume 
Gastrointestinal 
disorders 
Diarrhea 
Grade 1 or 2 – Continue at current 
dose 
Grade 3 – If grade 3 for >4 days, hold 
until recovery ≤ grade 2 then resume 
Grade 4 – Hold until recovery ≤ grade 
2 then resume 
 
11.2 Chemotherapy 


 
 
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The patient will discontinue FOLFOX and be referred for treatment off protocol if the 
patient requires dose reduction beyond level -2 during cycles 1-5 of preoperative 
therapy or if FOLFOX is held due to toxicity for more than 30 days from the previous 
cycle. 
 
The precise dose modification schema used and the symmetry of dose modification 
may be left to the discretion of the treatment physician. 
 
Table 11.2  FOLFOX dose levels 
Dose 
level* 
5-FU infusion 
5-FU bolus Oxaliplatin 
0 
1200 mg/m2/day x 2 days 
(2400 mg/m2 over 48 hours) 
400 mg/m2 
85 mg/m2 
-1 
960 mg/m2/day x 2 days 
(1920 mg/m2 over 48 hours) 
320 mg/m2 
65 mg/m2 
-2 
800 mg/m2/day x 2 days 
(1600 mg/m2 over 48 hours) 
270 mg/m2 
50 mg/m2 
-3 
680 mg/m2/day x 2 days 
(1360 mg/m2 over 48 hours) 
230 mg/m2 
40 mg/m2 
*Dose level 0 refers to the starting dose 
 
Table 11.3 FOLFOX dose modifications based on adverse events 
System/ 
organ/ 
class 
Adverse event 
Agent 
Dosage change 
Blood and 
lymphatic 
systemic 
disorders 
Neutropenia grade 
≥2 
 
and/or 
 
Thrombocytopenia 
grade ≥ 2 
5-FU 
Oxaliplatin 
Hold up to 16 days until ANC ≥ 1200 
K/mcL. If recovered in ≤ 16 days, 
then resume at next lower dose level. 
 
Hold up to 16 days until platelets ≥ 
75,000 K/mcL. If recovered in ≤ 16 
days, then resume at next lower dose 
level. 
Gastrointestinal 
disorders 
Nausea grade 2 
 
 
 
 
 
Nausea grade 3 
 
 
 
 
 
 
Oxaliplatin 
 
 
 
 
 
 
 
 
 
 
 
 
Intensify antiemetic therapy and 
proceed with FOLFOX at current 
dose level. Maximal antiemetic 
therapy includes a 5-HT inhibitor in 
addition to Compazine, lorazepam, 
aprepitant, and dexamethasone 
 
If resolved to < grade 2 on day of 
treatment, may proceed with 
intensification of antiemetic therapy 
and current dose level of FOLFOX. If 
not resolved to < grade 2 on day of 
therapy, intensify antiemetic regimen 


 
 
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Nausea grade 4 
 
 
 
 
 
 
 
 
Vomiting grade 2 
 
 
 
 
 
Vomiting grade 3 
 
 
 
 
 
 
 
 
Vomiting grade 4 
 
 
 
 
 
 
 
 
Diarrhea grade 2 
 
 
 
 
 
 
Diarrhea grade 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5-FU 
Oxaliplatin 
 
 
 
 
 
 
and proceed with FOLFOX when 
resolved to < grade 2. May decrease 
oxaliplatin one dose level if not 
responsive to maximal antiemetic 
support. 
 
If resolved to < grade 2 on day of 
treatment, may proceed with 
intensification of antiemetic therapy 
and current dose level of FOLFOX. If 
not resolved to < grade 2 on day of 
therapy, intensify antiemetic regimen 
and proceed with FOLFOX when 
resolved to < grade 2. Decrease 
oxaliplatin one dose level if not 
responsive to maximal antiemetic 
support. 
 
Intensify antiemetic therapy and 
proceed with FOLFOX at current 
dose level. Maximal antiemetic 
therapy includes a 5-HT inhibitor in 
addition to Compazine, lorazepam, 
aprepitant, and dexamethasone 
 
If resolved to < grade 2 on day of 
treatment, may proceed with 
intensification of antiemetic therapy 
and current dose level of FOLFOX. If 
not resolved to < grade 2 on day of 
therapy, intensify antiemetic regimen 
and proceed with FOLFOX when 
resolved to < grade 2. May decrease 
oxaliplatin one dose level if not 
responsive to maximal antiemetic 
support. 
 
If resolved to < grade 2 on day of 
treatment, may proceed with 
intensification of antiemetic therapy 
and current dose level of FOLFOX. If 
not resolved to < grade 2 on day of 
therapy, intensify antiemetic regimen 
and proceed with FOLFOX when 
resolved to < grade 2. Decrease 
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Diarrhea grade 4 
 
 
 
 
 
 
Oral mucositis, 
esophagitis, 
gastritis, pharyngeal 
mucositis, small 
intestinal mucositis, 
colitis, rectal and/or 
anal mucositis 
grade 3 
 
Oral mucositis, 
esophagitis, 
gastritis, pharyngeal 
mucositis, small 
intestinal mucositis, 
colitis, rectal and/or 
anal mucositis 
grade 4 
responsive to maximal antiemetic 
support. 
 
If resolved to < grade 2, intensify 
antidiarrheal therapy and proceed 
with FOLFOX at current dose level. If 
not resolved to < grade 2, hold 
FOLFOX, intensify antidiarrheal 
therapy and proceed with FOLFOX 
when resolved to < grade 2. 
 
If resolved to < grade 2, intensify 
antidiarrheal therapy and proceed 
with FOLFOX, decreasing 5FU and 
oxaliplatin one dose level.  If not 
resolved to < grade 2, hold FOLFOX, 
intensify antidiarrheal therapy and 
proceed with FOLFOX decreasing 
5FU one dose level when resolved to 
< grade 2. 
 
If resolved to < grade 2, intensify 
antidiarrheal therapy and proceed 
with FOLFOX, decreasing 5FU and 
oxaliplatin one dose level. If not 
resolved to < grade 2, hold FOLFOX 
decreasing 5FU and oxaliplatin one 
dose level when resolved to < grade 
2. 
 
Hold FOLFOX until mucositis 
improves to < grade 2 then resume 
with one dose level reduction of 5-FU 
and the previous dose level of 
oxaliplatin 
 
 
 
 
 
Hold FOLFOX until mucositis 
improves to < grade 2 then resume 
with two dose levels reduction of 5-
FU and the previous dose level of 
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Pulmonary 
disorders 
Cough, dyspnea, 
hypoxia, 
pneumonitis or 
pulmonary infiltrates 
grade 3+ 
5-FU 
Oxaliplatin 
Hold oxaliplatin until interstitial lung 
disease is ruled out. Continue 5-
FU/leucovorin. Discontinue study if 
interstitial lung disease is confirmed. 
Thrombotic 
microangiopathy 
Hemolytic uremic 
syndrome grade 3+ 
5-FU 
Oxaliplatin 
Discontinue oxaliplatin. Continue 5-
FU/leucovorin. 
Immune system 
disorders 
Allergic reaction 
grade 1 
 
 
Allergic reaction 
grade 2 
 
 
 
 
Allergic reaction 
grade 3 or 4 
Oxaliplatin 
Leucovorin 
Decrease infusion rate by 50% until 
symptoms resolve, then resume at 
initial planned rate. 
 
Stop FOLFOX infusion. Administer 
H1 and/or H2 blockers and/or 
steroids according to local medical 
site policy. Restart infusion when 
symptoms resolve and pretreat 
before all subsequent doses. 
 
Stop infusion. Discontinue FOLFOX. 
Skin and 
subcutaneous 
tissue disorders 
Extravasation 
Oxaliplatin 
Extravasation of oxaliplatin has been 
associated with necrosis. If 
extravasation is suspected, stop the 
FOLFOX infusion and restart at 
another site. 
Neurological 
Neurotoxicity grade 
2 persisting 
between treatment 
cycles 
 
Neurotoxicity grade 
3 resolving to 
≤grade 2 between 
treatment cycles 
 
Neurotoxicity grade 
3 persisting 
between treatment 
cycles 
 
Neurotoxicity grade 
4 
Oxaliplatin 
Continue FOLFOX with previous 
dose level of 5-FU and one dose level 
reduction of oxaliplatin for all 
subsequent cycles. 
 
Continue FOLFOX with previous 
dose level of 5-FU and one dose level 
reduction of oxaliplatin for all 
subsequent cycles. 
 
Discontinue oxaliplatin. Continue 5-
FU/leucovorin. 
 
 
 
Discontinue oxaliplatin. 
Continue 5-FU/leucovorin. 
Other non-
hematologic 
Grade 3 or 4 
5-FU 
Oxaliplatin 
Leucovorin 
Hold FOLFOX until toxicity ≤grade 1 
then resume with one dose level 
reduction of both 5-FU and 
oxaliplatin. 
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Omit = Treatment is not given for this cycle 
Hold = Treatment can be made up as part of this cycle 
Discontinue = Treatment is totally stopped 
 
12.0   PATIENT DISCONTINUATION 
Patients may discontinue study treatment at any time.  Any patient who discontinues 
treatment will be encouraged to return to the study center to undergo treatment 
discontinuation assessments.  The primary reason for discontinuation should be 
documented. 
 
Reasons for discontinuation of a patient by the investigator include, but are not limited 
to, the following: 
 Documented disease progression or <20% clinical response to LDFRT-FOLFOX  
 Symptomatic progression, characterized by increasing tenesmus or 
hematochezia, decreasing stool caliber, or other signs of imminent bowel 
obstruction. 
 Patient not able or willing to complete the prescribed radiation therapy. 
 Patient not able or willing to complete 6 cycles of neoadjuvant FOLFOX. 
 Patient non-compliance. 
 Patient withdraws consent to participate in the study. 
 Persistent (≥ 3 weeks) NCI CTCAE version 4.0 grade 3-4 adverse event or any 
significant adverse event that compromises the patient’s ability to participate in 
the study. 
 Investigator determination that it is not in the patient’s best interest to continue 
participation. It is the right and duty of the Investigator to interrupt the treatment 
of any subject whose health or well-being may be threatened by continuation in 
this study.  Such subjects should be withdrawn from the study and referred for 
standard of care treatment. 
 
13.0  PHARMACOLOGY 
 
13.1  Oxaliplatin (Eloxatin®, OXAL) 
13.1.1 Background:  Oxaliplatin, a platinum derivative, is an alkylating agent.  
Following intracellular hydrolysis, the platinum compound binds to DNA forming 
cross-links which inhibit DNA replication and transcription, resulting in cell death.  
Cytotoxicity is cell-cycle nonspecific. 
 
13.1.2 Formulation:  Commercially available for injection as: 
Solution [preservative free]: 5 mg/mL (10 mL, 20 mL, 40 mL). 
 
13.1.3 Preparation, storage, and stability:  Refer to package insert for 
complete preparation and dispensing instructions.  Store intact vials in original 
outer carton at room temperature and do not freeze.  According to the 
manufacturer, solutions diluted for infusion are stable up to 6 hours at room 
temperature or up to 24 hours under refrigeration.  Oxaliplatin solution diluted 
with D5W to a final concentration of 0.7 mg/mL (polyolefin container) has been 


 
 
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shown to retain > 90% of its original concentration for up to 30 days when 
stored at room temperature or refrigerated; artificial light did not affect the 
concentration (Andre, 2007).  As this study did not examine sterility, 
refrigeration would be preferred to limit microbial growth.  Do not prepare using 
a chloride-containing solution (e.g., NaCl).  Dilution with D5W (250 or 500 mL) 
is required prior to administration.  Infusion solutions do not require protection 
from light. 
 
13.1.4 Administration:  Refer to the treatment section for specific administration 
instructions.  Administer as IV infusion over 2-6 hours.  Flush infusion line with D5W 
prior to administration of any concomitant medication.  Patients should receive an 
antiemetic premedication regimen.  Cold temperature may exacerbate acute 
neuropathy.  Avoid mucositis prophylaxis with ice chips during oxaliplatin infusion. 
 
13.1.5 Pharmacokinetic information:   
Distribution: Vd: 440 L.   
Protein binding: > 90% primarily albumin and gamma globulin (irreversible binding to 
platinum).   
Metabolism: Nonenzymatic (rapid and extensive), forms active and inactive 
derivatives.   
Half-life elimination: Terminal: 391 hours; Distribution: Alpha phase: 0.4 hours, Beta 
phase: 16.8 hours.  
Excretion: Primarily urine (~ 54%); feces (~ 2%). 
 
13.1.6 Potential Drug Interactions 
13.1.6.1 Increased Effect/Toxicity:  Nephrotoxic agents may increase 
oxaliplatin toxicity.  When administered as sequential infusions, observational 
studies indicate a potential for increased toxicity when platinum derivatives 
(carboplatin, cisplatin, oxaliplatin) are administered before taxane derivatives 
(docetaxel, paclitaxel). 
13.1.6.2 Decreased Effect:  Oxaliplatin may decrease plasma levels of digoxin. 
 
13.1.7 Drug procurement:  Commercial supplies.  Pharmacies or clinics shall 
obtain supplies from established commercial supply chain or wholesaler. 
 
13.1.8 Nursing guidelines 
13.1.8.1 GI adverse events similar to cisplatin occurs with doses above 30 
mg/m2.  It can be almost constant and frequently severe, but not always dose 
limiting.  Monitor for nausea and vomiting and treat accordingly. 
13.1.8.2  Dose-limiting side effects can be paresthesias of hands, fingers, toes, 
pharynx, and occasionally cramps which develops with a dose-related 
frequency (>90 mg/m2).  Duration of symptoms tend to be brief (less than a 
week) with the first course, but longer with subsequent courses.  Phase I 
patients have reported exacerbation of paresthesias by touching cold surfaces 
or exposure to cold.  Advise patient of these possibilities and instruct patient to 
report these symptoms to the health care team.  Also advise patient to refrain 


 
 
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from operating dangerous machinery that requires fine sensory-motor 
coordination, if symptoms appear. 
13.1.8.3 Oxaliplatin is incompatible with NS.  Flush lines with D5W prior to and 
following oxaliplatin infusion. 
13.1.8.4 Low back pain is a common side effect, perhaps a form of 
hypersensitivity reaction.  Instruct patient in good body mechanics, advise light 
massage, heat, etc. 
13.1.8.5 Laryngopharyngeal dysesthesia (LPD) occurs in about 15% of patients 
and is acute, sporadic, and self-limited.  It usually occurs within hours of 
infusion, is induced or exacerbated by exposure to cold, and presents with 
dyspnea and dysphagia.  The incidence and severity appear to be reduced by 
prolonging infusion time.  Instruct patient to avoid ice and cold drinks the day of 
infusion.  If ≥ Grade 2 laryngopharyngeal dysesthesia occurs during the 
administration of oxaliplatin, do the following: 
 Stop oxaliplatin infusion. 
 Administer benzodiazepine and give patient reassurance. 
 Test oxygen saturation via a pulse oximeter. 
 At the discretion of the investigator, the infusion can be restarted at 1/3 the 
original rate of infusion. 
 Rapid resolution is typical within minutes to a few hours.  Can recur with 
retreatment. 
13.1.8.6 Patients receiving oxaliplatin on this study should be counseled to avoid 
cold drinks, chewing ice chips, and exposure to cold water or air because the 
sensory neurotoxicity often seen with oxaliplatin appears to be exacerbated by 
exposure to cold.  The period of time during which the patient is at risk for these 
cold-induced sensory neuropathies is not well documented.  Patients should 
exercise caution regarding cold exposure during the treatment period. 
 
13.2  Leucovorin 
13.2.1 Background:  A reduced form of folic acid, leucovorin supplies the 
necessary cofactor blocked by methotrexate, enters the cells via the same active 
transport system as methotrexate.  Stabilizes the binding of 5-dUMP and 
thymidylate synthetase, enhancing the activity of fluorouracil. 
 
13.2.2 Formulation:  Commercially available as powder for reconstitution: 50 mg, 
100 mg, 200 mg, 350 mg.  Injection, solution: 10 mg/mL (50 mL). 
 
13.2.3 Preparation, storage, and stability:  Powder for injection:  Store at room 
temperature, protect from light.  Reconstitute with sterile water for injection or 
bacteriostatic water for injection; dilute in 100-1000 mL 0.9% NaCl or D5W.  When 
doses > 10 mg/m2 are required, reconstitute using sterile water for injection, not a 
solution containing benzyl alcohol.  Solutions reconstituted with bacteriostatic water 
for injection must be used within 7 days. 
 
13.2.4 Nursing Guidelines 
13.2.4.1 Headache may occur.  Advise patient analgesics such as Tylenol 


 
 
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may help.  Instruct patient to report any headache that is unrelieved. 
13.2.4.2 Observe for sensitization reaction (rash, hives, pruritus, facial flushing 
and wheezing). 
13.2.4.3 May potentiate the toxic effects of fluoropyrimidine (5-FU) therapy, 
resulting in increased hematologic and gastrointestinal side effects (diarrhea, 
stomatitis).  Monitor closely. 
13.2.4.4 May cause mild nausea or upset stomach.  Administer antiemetics 
if necessary and evaluate for their effectiveness. 
 
13.3  Fluorouracil (Adrucil, Efudex, [5FU]) 
13.3.1 Background:  Antineoplastic Agent, Antimetabolite (Pyrimidine Analog).  
Fluorouracil is a fluorinated pyrimidine antimetabolite that inhibits thymidylate 
synthetase, blocking the methylation of deoxyuridylic acid to thymidylic acid, 
interfering with DNA, and to a lesser degree, RNA synthesis.  Fluorouracil appears 
to be phase specific for the G1 and S phases of the cell cycle. 
 
13.3.2 Formulation:  Commercially available for injection 50 mg/mL (10 mL, 20 mL, 
50 mL, and 100 mL). 
 
13.3.3 Preparation, storage, and stability:  Store intact vials at room 
temperature and protect from light.  A slight discoloration may occur with 
storage but usually does not denote decomposition.  Dilute in 50-1000 mL of 
0.9% NaCl or D5W.  If exposed to cold, a precipitate may form; gentle heating 
to 60ºC will dissolve the precipitate without impairing the potency.  Solutions 
in 50-1000 mL 0.9% NaCl or D5W or undiluted solutions in syringes are 
stable for 72 hours at room temperature.  Fluorouracil should not be co-
administered with diazepam, doxorubicin, daunorubicin, idarubicin, cisplatin, 
or cytarabine.  However, fluorouracil and leucovorin are compatible for 14 
days at room temperature.  Fluorouracil is compatible with vincristine, 
methotrexate, and cyclophosphamide. 
 
13.3.4 Administration:  Fluorouracil may be given IV push, IV infusion. 
 
13.3.5 Pharmacokinetic information:  Distribution:  Vd ~ 22% of total body water; 
penetrates extracellular fluid, CSF and third space fluids (e.g., pleural effusions and 
ascitic fluid).  Metabolism:  Hepatic (90%); via a dehydrogenase enzyme; 
Fluorouracil must be metabolized to be active.  Half-life elimination:  Biphasic:  Initial: 
6-20 minutes; two metabolites, FdUMP and FUTP, have prolonged half-lives 
depending on the type of tissue. 
 
 
13.3.6 Nursing Guidelines 
13.3.6.1 Monitor complete blood count and platelet count.  Instruct patient to 
report signs and symptoms of infection, unusual bruising or bleeding to the 
physician. 
13.3.6.2 Administer antiemetics as needed for nausea. 


 
 
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13.3.6.3 Diarrhea may be dose-limiting; encourage fluids and treat 
symptomatically. 
13.3.6.4 Assess for stomatitis; oral care measures as indicated. 
13.3.6.5 Monitor for neurological symptoms (headache, ataxia). 
13.3.6.6 Inform patient of potential alopecia. 
13.3.6.7 Those patients on continuous infusion may need instruction 
regarding central intravenous catheters and portable intravenous or IA 
infusion devices. 
13.3.6.8 5-FU-induced conjunctivitis is a common problem.  Advise patient to 
report any eye soreness or redness to the healthcare team. 
13.3.6.9 Photosensitivity may occur.  Instruct patients to wear sunblock when 
outdoors. 
 
14.0  STATISTICS 
 
Our hypothesis is that preoperative concurrent LDFRT and FOLFOX will result in a pCR 
rate of at least 35%.  Thus our power analysis will rely on precision related to estimating 
the CR rate.  Additionally, given that we will use the information from this study to 
design a prospective experimental study, we seek to enroll 30 patients within 24 
months.  As such, a sample size of 30 patients produces a two-sided 95% confidence 
interval with a width equal to 0.36 when the CR rate is 35%. 


 
 
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APPENDIX I 
 
GCC 1314       HP-00060641      STUDY SCHEDULE (v. 13March 2017) 
 
 
C = Conventional Care 
R = Research 
a       ≤ 28 days prior to registration 
b       ≤ 14 days prior to registration 
Procedures 
Prior to study 
Chemo-RT 
Day 1  
of each cycle  
(6 cycles 
total) 
(≤ 2 days) 
Restaging 
(3-5 weeks) 
after completion 
of chemo-LDFRT 
Surgery 
(6-8 weeks)  
after completion 
of chemo-LDFRT 
Informed Consent 
R 
 
 
 
History and Physical exam 
  C a 
C 
C 
 
Performance Status 
C 
C 
C 
 
Evaluation by Surg Onc, Med Onc, Rad Onc 
  C a 
 
C 
 
Toxicity Evaluation 
 
C 
C 
 
Weight, BSA 
C 
C 
C 
 
Height 
C 
 
 
 
CBC with differential and platelets 
  C b 
C 
C 
 
CMP 
(Alb, TBili, Ca, Cl, CO2, Creatinine, G, TP,  
Na, K, BUN, AlkPhos, AST, ALT) 
  C b 
C 
C 
 
CEA 
  C b 
 
C 
 
CT chest or chest x-ray AND CT abdomen or 
MRI abdomen 
 Ca 
 
C 
 
MRI pelvis with and without contrast or ERUS 
  C a 
 
C 
 
Endoscopy (proctoscopy, sigmoidoscopy, 
colonoscopy) 
C 
 
C 
 
Serum pregnancy test B-HCG 
  C b 
 
 
 
PT/INR/PTT 
 
 
C 
 
TME path evaluation 
 
 
 
C 


 
 
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APPENDIX II 
 
http://www.ecog.org/general/perf_stat.html 
 
ECOG PERFORMANCE STATUS 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
5 
Dead 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. 
 
Credit given to the Eastern Cooperative Oncology Group (ECOG), Robert Comis, M.D., 
Group Chair. 
 
 
 
 
 
 
 


 
 
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APPENDIX III 
 
NCI CTCAE version 4.0 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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APPENDIX IV 
 
AJCC 7th Edition Rectum Cancer Staging Definitions 
Source: The AJCC Cancer Staging Manual, 7th Edition (2010) published by Springer 
New York, Inc. 
 
Primary Tumor (T) 
TX Primary tumor cannot be assessed 
T0 No evidence of primary tumor 
Tis Carcinoma in situ: intraepithelial or invasion of lamina propria1 
T1 Tumor invades submucosa 
T2 Tumor invades muscularis propria 
T3 Tumor invades through the muscularis propria into pericolorectal tissues 
T4a Tumor penetrates to the surface of the visceral peritoneum2 
T4b Tumor directly invades or is adherent to other organs or structures2,3 
 
Regional Lymph Nodes (N)4 
NX Regional lymph nodes cannot be assessed 
N0 No regional lymph node metastasis 
N1 Metastasis in 1–3 regional lymph nodes 
N1a Metastasis in one regional lymph node 
N1b Metastasis in 2–3 regional lymph nodes 
N1c Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or 
perirectal tissues without regional nodal metastasis 
N2 Metastasis in 4 or more regional lymph nodes 
N2a Metastasis in 4–6 regional lymph nodes 
N2b Metastasis in 7 or more regional lymph nodes 
 
Distant Metastasis (M) 
M0 No distant metastasis 
M1 Distant metastasis 
M1a Metastasis confined to one organ or site (for example, liver, lung, ovary, 
nonregional node) 
M1b Metastases in more than one organ/site or the peritoneum 
 
Notes: 
1 Tis includes cancer cells confined within the glandular basement membrane 
(intraepithelial) or mucosal lamina propria (intramucosal) with no extension through the 
muscularis mucosae into the submucosa. 
2 Direct invasion in T4 includes invasion of other organs or other segments of the 
colorectum as a result of direct extension through the serosa, as confirmed on 
microscopic examination (for example, invasion of the sigmoid colon by a carcinoma of 
the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion 
of other organs or structures by virtue of extension beyond the muscularis propria (that 
is, a tumor on the posterior wall of the descending colon invading the left kidney or 


 
 
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lateral abdominal wall; or a mid or distal rectal cancer with invasion of prostate, seminal 
vesicles, cervix, or vagina). 
3 Tumor that is adherent to other organs or structures, grossly, is classified cT4b. 
However, if no tumor is present in the adhesion, microscopically, the classification 
should be pT1-4a depending on the anatomical depth of wall invasion. The V and L 
classifications should be used to identify the presence or absence of vascular or 
lymphatic invasion, whereas the PN site-specific factor should be used for perineural 
invasion. 
4 A satellite peritumoral nodule in the pericolorectal adipose tissue of a primary 
carcinoma without histologic evidence of residual lymph node in the nodule may 
represent discontinuous spread, venous invasion with extravascular spread (V1/2), or a 
totally replaced lymph node (N1/2). Replaced nodes should be counted separately as 
positive nodes in the N category, whereas discontinuous spread or venous invasion 
should be classified and counted in the Site-Specific Factor category Tumor Deposits 
(TD). 
 
 
 
Note: cTNM is the clinical classification, pTNM is the pathologic classification. 


 
 
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