Clinical trial NCT00745134
Conditions: Rectal Mucinous Adenocarcinoma Rectal Signet Ring Cell Adenocarcinoma Recurrent Rectal Carcinoma Stage IIA Rectal Cancer AJCC v7 Stage IIB Rectal Cancer AJCC v7 Stage IIC Rectal Cancer AJCC v7 Stage IIIA Rectal Cancer AJCC v7 Stage IIIB Rectal Cancer AJCC v7 Stage IIIC Rectal Cancer AJCC v7
Sponsor: M.D. Anderson Cancer Center
Start date: 2008-08-11; Completion date: 2022-11-11
Enrollment: 22 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well radiation therapy and capecitabine with or without curcumin before surgery works in treating patients with rectal cancer. Drugs such as curcumin may make tumor cells more sensitive to radiation therapy. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy with radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known whether chemotherapy and radiation therapy is more effective with or without curcumin when given before surgery in patients with rectal cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the efficacy of a combination of capecitabine and radiation therapy with or without curcumin in locally advanced rectal cancer as assessed by pathological complete response rate.

SECONDARY OBJECTIVES:

I. To determine downstaging, local control, disease-free survival and overall survival rates.

II. To determine serum and rectal tumor tissue pharmacology of curcumin and its metabolites in the above patients and its correlation with clinical response.

III. To identify surrogate molecular markers for curcumin effects. IV. To correlate serum cytokine levels with quality of life in patients receiving this therapy.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo radiation therapy 5 days a week for a total of 28 fractions. Patients also receive capecitabine orally (PO) twice daily (BID) on the days of radiation therapy and curcumin PO BID in weeks 1-11.5.

ARM II: Patients undergo radiation therapy and receive capecitabine as in Arm I. Patients also receive placebo PO BID in weeks 1-11.5.

After completion of study treatment, patients are followed up at 1 month.

Arms: arm 1: Patients undergo radiation therapy 5 days a week for a total of 28 fractions. Patients also receive capecitabine PO BID on the days of radiation therapy and curcumin PO BID in weeks 1-11.5. arm 2: Patients undergo radiation therapy and receive capecitabine as in Arm I. Patients also receive placebo PO BID in weeks 1-11.5.
Interventions: intervention 1: Capecitabine intervention 2: Curcumin intervention 3: Laboratory Biomarker Analysis intervention 4: Pharmacological Study intervention 5: Placebo intervention 6: Quality-of-Life Assessment intervention 7: Radiation Therapy
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Correlative studies intervention 4: Optional correlative studies intervention 5: Given PO intervention 6: Ancillary studies intervention 7: Undergo radiation therapy

Protocol documents:
Prot_SAP_000.pdf: 
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Protocol Body
1.0 Objectives
1.1
The primary objective of this study is to evaluate the efficacy of a combination of 
capecitabine and radiation therapy with or without curcumin in locally advanced rectal 
cancer as assessed by pathological complete response rate.
1.2
Secondary objectives include: 
1.2.1
To determine downstaging, local control, disease-free survival and overall survival 
rates.
1.2.2
To determine serum and rectal tumor tissue pharmacology of curcumin and its 
metabolites in the above patients and its correlation with clinical response.
1.2.3
To  identify surrogate molecular markers for curcumin effects.
1.2.4
To correlate serum cytokine levels with quality of life in patients receiving this 
therapy.
2.0 Background
Rectal cancer:  Rectal cancer occurs in about 35,000 patients in the United States per year, 
accounting for about 30% of the cancers in the large bowel (1).  Surgery is the most important 
component of treatment for rectal cancer and generally entails removal of the involved rectum 
with margins and with its vascular supply and lymphatic drainage.  Standard treatment for early 
stage cancers is surgical resection alone.  However, most rectal cancers seen in the clinic are 
locally advanced and some are metastatic.  The German rectal cancer trial, along with multiple 
Phase II clinical trials, has established pre-operative chemoradiation therapy (CRT) as the 
standard of care for locally advanced rectal cancer patients (2-4).  Compared to post-operative 
chemoradiation, pre-operative chemoradiation increases local control and sphincter 
preservation rates, and is associated with lower rates of acute and late toxicity.  In the German 
rectal cancer trial, 8% of patients treated with pre-operative chemoradiation had a pathological 
complete response (pCR), and the 5-year local recurrence rate in patients treated with 
preoperative chemoradiation was 6%. The 5-year disease-free survival (DFS) and overall 
survival (OS) rates were 68% and 76%.  By comparison, over 500 rectal cancer patients have 
been treated at M.D. Anderson Cancer Center with preoperative chemoradiation in the past 
decade.  In this series, the pathologic complete response rate was 19% with downstaging rate 
of 57%, and 5-year local recurrence rates of 10%; the corresponding 5-year DFS and OS 
survival rates were 79% and 80%, respectively (3, 5).  We and other groups have recognized 
that response to pre-operative CRT is an excellent predictor of better DFS and OS rates (6-10).  
The median DFS and overall survival rates for responders were 46 months and 47 months, 
respectively; for non-responders these outcome measures were 38 months and 41 months, 
respectively (6).  In addition, response to pre-operative CRT may improve the chances of 
sphincter-preserving surgery (11, 12).  Lastly, a complete pathological response to CRT may 
permit selected patients to undergo less extensive resections, further minimizing toxicity (13).  
Our goal is to further increase the pCR rate and downstaging rate, which we will use as 
surrogates for overall clinical outcomes.  Strategies include increasing the dose of radiation 
without increasing surgical morbidity, and optimizing systemic therapy during radiation.   
Building on the radiobiological advantage documented in head and neck cancer, we have 
increased the intensity of radiation therapy by delivering two doses of radiation therapy 
(concomitant boost) during the last week of the pre-operative regimen (4, 14, 15).  This resulted 
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in a pCR rate of 18%, no different from that of prior experiences.  We are presently investigating 
the combination of standard fluoropyrimidine-based chemotherapy with anti-angiogenic therapy 
using Bevacizumab.  Other groups have combined newer targeted agents to the cytotoxic 
backbone of radiation therapy and fluoropyrimidine-based chemotherapy (16-18).  No regimen 
has successfully improved overall outcomes and many have increased toxicity.  Most strategies 
that target radioresistance of tumors have focused on the inherently or constitutively 
overexpressed pro-survival pathways within tumor cells (19, 20).  Multiple signaling pathways 
and redundancies, however, make it difficult to overcome the blockade of a specific pathway 
(21, 22).  An alternative approach that has interested us is broad-spectrum blockade of 
inducible pathways that transiently drive pro-survival and anti-apoptotic signals to overcome the 
cytotoxic signal triggered by treatment.  An agent of particular interest in this regard is curcumin. 
Curcumin: Curcumin (diferuloylmethane) is a polyphenol, and is the major constituent of the 
yellow spice turmeric, derived from the rhizomes of Curcuma longa. The medicinal use of this 
plant has been documented in Ayurveda, the Indian system of medicine, for centuries (23, 24). 
It is commonly used as a spice or flavoring agent, and has been widely utilized in India and 
southeast Asia mainly for its anti-inflammatory properties. While the anti-inflammatory properties 
of curcumin have been demonstrated in the scientific literature decades ago, more recently 
curcumin has shown potential anti-neoplastic and chemopreventive promise in a number of in 
vitro, in vivo and clinical studies (25, 26). Curcumin has been shown to inhibit the proliferation of 
a wide variety of tumor cells (27-34). It inhibits angiogenesis, induces apoptosis or cell cycle 
arrest, and causes regression of tumors in preclinical models (28-32, 35-37). 
Mechanism of anti-tumor activity of curcumin:  Although the exact mechanisms for its 
anti-tumor properties are not fully understood, extensive research indicates that curcumin 
inhibits a number of molecular pathways that contribute to cell survival, proliferation, invasion, 
and metastasis of cancer cells.  This includes inhibition of signal transduction pathways and 
tumor angiogenesis and induction of apoptosis (27-34). Studies from our group and others have 
shown that activation of nuclear factor kappa B (NF-kB) promotes cell survival and cell 
proliferation, whereas downregulation of NF-kB sensitizes cells to apoptosis (38-44). Thus, 
suppression of NF-kB in cancer cells may provide a molecular target for prevention and 
treatment of cancer (40, 45-49). Our group and others have shown that curcumin is a potent 
down regulator of NF-kB activation, most likely through suppression of inhibitor of NF-kB (IkB) 
kinase activity, and inhibition of NF-kB mediated gene expression (25, 27-30, 32, 36, 50-55). In 
keeping with these proliferative signals induced by NF-kB, constitutive activation of NF-B is 
found in many malignancies including colorectal cancer (56, 57).  NF-kB regulated genes 
include bcl-2, cyclo-oxygenase-2 (COX2), matrix-metalloproteinase-9 (MMP-9), and adhesion 
molecules such as ICAM-1 and VCAM-1 (58).   Since NF-kB regulates several genes that are 
involved in cellular transformation, proliferation, invasion, and angiogenesis, suppression of 
NF-kB activation may be one of the mechanisms of actions by which curcumin mediates its 
anti-tumor effects.  Additionally, it inhibits induction of COX2, an enzyme implicated in colorectal 
carcinogenesis (59-61).  This is best explained by inhibition of IkB kinase (IKK) activity which is 
responsible for IkB phosphorylation (54).
In addition, curcumin affects other signaling mechanisms that are critical for tumor growth 
including inhibition of epidermal growth factor receptor (EGFR) signaling and tyrosine kinase 
activity and downregulation of the transcription factor c-Jun/AP-1 and STAT3, which may 
account for the inhibitory effects of curcumin on proliferation of various tumor cell lines (62-67).  
Specifically in colorectal cancer, curcumin stimulates the transactivating activity of peroxisome 
proliferator-activated receptor  which appears to mediate suppression of EGFR and cyclin D1 
genes (68).  Curcumin also has immunomodulatory effects mediated via activation of host 
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macrophages and natural killer cells and modulation of lymphocyte-mediated function (69, 70).  
Therefore, the exact mechanism of action of curcumin remains inadequately explained.  
However, the most consistent finding is that curcumin induces apoptosis.  This may be 
mediated by impairment of the ubiquitin proteasome pathway (71), upregulation of 
proto-oncoprotein Bax (72, 73), activation of caspases and induction of Fas receptor 
aggregation in a FasL dependent manner (73), and the generation of free radicals (74).  
The NF-kB pathway:
NF-kB resides in the cytoplasm of cells in the inactive state in a complex with inhibitors of kB 
(IkBs).  NF-kB is activated by phosphorylation of IkB-a at two serine residues (Ser-32 and –36) 
or, less frequently, at a tyrosine residue (Tyr-42) by IkB kinases leading to its ubiquitination and 
degradation by the proteosome complex.  This leads to release of the active NF-kB, which 
translocates to the nucleus and binds to its consensus sequence in the promoter or enhancer 
region.  This further leads to transcription of a wide variety of anti-apoptotic genes and other 
pleiotropic effects.  The usual triggers for NF-kB activation are cytokines such as IL-1 and 
TNF-a, bacterial or viral infections, growth factors acting via the atypical kinase (Akt) pathway, 
and stress (including reactive oxygen intermediates and ionizing radiation).  The effector 
proteins include acute phase reaction proteins, cytokines, adhesion molecules and feedback 
regulatory proteins that moderate the NF-kB response.  In colorectal cancer in particular, 
cyclo-oxygenase-2 (cox-2) is a key mediator of tumor progression whose expression is also 
mediated by NF-kB. 
Targeting inducible- rather than constitutive- pro-survival pathways as a means to 
enhance radioresponse:  Tumors that constitutively overexpress pro-survival signaling 
molecules are well characterized as more resistant to radiation therapy than those with normal 
or low expression levels.  This is a classical target for radiosensitization strategies including 
newer therapies that target epidermal growth factor receptor, restore p53, block bcl-2, and 
target Ras.  The efficacy of highly targeted therapy may be diminished by up-regulation of 
redundant signaling pathways that signal downstream of the initial targeting and overcome such 
blockade.  For instance, in a study of gliomas cells using a targeted inhibitor of the EGFR 
pathway, cells upregulated insulin-like growth factor receptor-1, which then triggered signaling 
downstream  (PI3kinase/Akt and Ras/MAPK pathways) from the initial EGFR inhibition to 
overcome this blockade (21).  An alternative strategy to enhance radioresponse is to target 
inducible radioresistance pathways.  These are often transiently up-regulated in response to 
radiation therapy and can provide the necessary stimuli to increase proliferation and inhibit 
apoptosis.  This response is very similar to classical radiobiology principles of radioresistance 
where repopulation (proliferation of tumor cell clonogens between two fractions of sublethal 
radiation therapy) leads to decrease in effectiveness of a course of radiation therapy.  This is 
illustrated by the cartoon in Figure 1 showing the theoretical effect of tumor repopulation on 
tumor control probability after a 30-day course of fractionated radiation therapy. In each curve, 
50% cell killing was assumed for each dose of radiation. Continued cell proliferation (50% 
re-growth was assumed) results in partial tumor repopulation between fractions of radiation 
(light line). Pharmacologic inhibition of tumor repopulation (dark line) could significantly improve 
the efficacy of therapy. 
We have demonstrated in preclinical studies that NF-kB provides one such pro-survival, 
anti-apoptotic signal that is induced transiently by radiation therapy and protects cells from 
radiation-induced apoptosis (see preliminary results) (75).  Colorectal cancers are known to 
have low baseline constitutive NF-kB activity and our preclinical studies have shown that this is 
further activated by radiation therapy.  Targeting this radiation-induced pro-survival signaling 
pathway is a novel method to potentiate radioresponse.  We have demonstrated that curcumin 
inhibits this radiation-induced NF-kB activation and increases radioresponse of colorectal 
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cancer cells.  Consequently, our proposal to use a non-toxic broad-spectrum agent, 
curcumin, to target an inducible radioresistance pathway, the NF-kB pathway, is both 
novel and logical.  
Fig. 1: Theoretical effect of tumor 
re-population on tumor control probability. 
Epidemiological significance: The higher prevalence of colorectal cancer in the Western 
world is attributed to dietary factors including higher intake of animal fat and lower intake of 
fiber.  This is supported by the finding that Japanese immigrants to the United States have a 
greater than 2-fold increase in the development of colorectal cancer than native Japanese.  
Decreased prevalence in Asian and African countries where fiber and cellulose are consumed 
in greater quantities also supports the role of dietary factors in colorectal carcinogenesis.  Within 
India, the incidence of colorectal cancer is higher in Northern India than Southern India.  One 
possible explanation is the increased consumption of curry-containing foods in South India, 
where the coloring agent turmeric is used.
Capecitabine:  A randomized trial by the Gastrointestinal Intergroup established protracted 
venous infusional 5-FU as the standard concurrent chemotherapy with radiation (76).  Oral 
capecitabine pharmacologically mimics protracted venous infusional 5-FU.   A recent phase III 
trial on adjuvant therapy for stage III colon cancer showed that capecitabine gave equivalent 
disease-free survival as bolus 5-FU/leukovorin, with a trend towards improved disease-free 
survival and overall survival, as well as decreased neutropenia and stomatitis (77).   
Capecitabine is well tolerated with radiotherapy based on data from a phase I dose escalation 
trial in patients with rectal cancer (78). Capecitabine was administered continuously (7 days per 
week) throughout a 38-day course of radiotherapy (50.4 Gy in 28 fractions).  The dose limiting 
toxicity was hand foot syndrome, and there was significantly less gastrointestinal and 
hematologic toxicity than expected from infusional 5-FU.  At M.D. Anderson, capecitabine has 
been studied in a phase II trial in patients with rectal cancer treated with neoadjuvant therapy.  
Our results indicate that therapy is very well tolerated and the treatment effect is comparable to 
5-FU (15). 
MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI)
The MDASI is a simple, reliable, and patient self-reported, clinically validated tool for the 
assessment of symptom burden and symptom clusters in patients undergoing treatment for cancer. 
Using serial administration of the MDASI during a course of RT for rectal cancer, we are able to 
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generate plots that represent the severity and temporal profile of individual components of a 
symptom cluster. This has been done on prior novel biological agent and/or radiation fractionation 
protocols of chemoradiation for rectal cancer and is also being performed on a separate quality of 
life protocol on all patients treated with chemoradiation for rectal cancer.  The MDASI - 
gastrointestinal module (MDASI-GI) is an extension of the MDASI with questions specifically 
addressing GI symptoms experienced by cancer patients during chemotherapy and/or radiaiton 
therapy.  The additional questions are being validated in an on-going collection of questionnaires 
during chemoradiation for rectal cancer.  Similarly, the BFI was developed for the rapid assessment 
of fatigue severity for use in both clinical screening and clinical 
trials. The BFI has been shown 
to be simple, completable by most patients, and an internally stable (reliable) measure of the 
severity of fatigue that correlates highly with similar fatigue measures. Both the MDASI and BFI 
questionnaires will be given to the patients by the research nurse and will be filled out by the patient 
and/or their caregiver. These questionnaires are filled weekly during radiation treatment and the 
completed questionnaires are handed to the research nurse during weekly treatment visits with the 
treating radiation oncologist.
3.0 Drug Background
3.1
Capecitabine
3.1.1
Description
Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity. It is an 
orally administered systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) which 
is converted to 5-fluorouracil.
The chemical name for capecitabine is 5’-deoxy-5-fluoro-N-[(pentyloxy) 
carbonyl]-cytidine and has a molecular weight of 359.35. Capecitabine has the 
following structural formula:
O
OH
H3C
HO
O
O
N
N
O
NH
F
Capecitabine is a white to off-white crystalline powder with an aqueous solubility of 
26 mg/mL at 20ºC.
Capecitabine  is supplied as biconvex, oblong film-coated tablets for oral 
administration. Each light peach-colored tablet contains 150 mg capecitabine and 
each peach-colored tablet contains 500 mg capecitabine. The inactive ingredients 
in capecitabine include: anhydrous lactose, croscarmellose sodium, hydroxypropyl 
methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. 
The peach or light peach film coating contains hydroxypropyl methylcellulose, talc, 
titanium dioxide, and synthetic yellow and red iron oxides.
Drug Formulation, Packaging, and Storage
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Capecitabine is commercially available as 150 mg or 500 mg tablets. Capecitabine 
tablets are packed in polyethylene bottles, containing either 120 x 150 mg tablets 
or 240 x 500 mg tablets.  Capecitabine tablets should be stored at room 
temperature (15 to 30C) in the container in which they are provided.
3.1.2
Clinical Pharmacology
Capecitabine is relatively non-cytotoxic in vitro. This drug is enzymatically 
converted to 5-fluorouracil (5-FU) in vivo.
Bioactivation: Capecitabine is readily absorbed from the gastrointestinal tract. In 
the liver, a 60 kDa carboxylesterase hydrolyzes much of the compound to 
5’-deoxy-5-fluorocytidine (5’-DFCR). Cytidine deaminase, an enzyme found in most 
tissues, including tumors, subsequently converts 5’-DFCR to 
5’-deoxy-5-fluorouridine (5’-DFUR). The enzyme, thymidine phosphorylase 
(dThdPase), then hydrolyzes 5’-DFUR to the active drug 5-FU. Many tissues 
throughout the body express thymidine phosphorylase. Some human carcinomas 
express this enzyme in higher concentrations than surrounding normal tissues.
Metabolic Pathway of capecitabine to 5-FU
dThdPase
Cyd deam inase
Carboxylesterase
Capecitabine
N
N
O
O
NH-CO-O
F
OH
HO
H3C
5’-DFCR
F
N
N
O
O
OH
HO
NH 2
H 3C
5-FU
HN
NH
O
O
F
5’-DFUR
HN
N
O
O
O
F
OH
HO
H 3C
3.1.3 Mechanism of Action: 
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Both normal and tumor cells metabolize 5-FU to 5-fluoro-2’-deoxyuridine 
monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). These 
metabolites cause cell injury by two different mechanisms. First, FdUMP and the 
folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase 
(TS) to form a covalently bound ternary complex. This binding inhibits the formation 
of thymidylate from 2’-deoxyuridylate. Thymidylate is the necessary precursor of 
thymidine triphosphate, which is essential for the synthesis of DNA, so that a 
deficiency of this compound can inhibit cell division. Second, nuclear 
transcriptional enzymes can mistakenly incorporate FUTP in place of uridine 
triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere 
with RNA processing and protein synthesis.
3.1.4 Pharmacokinetics in Colorectal Tumors and Adjacent Healthy Tissue: 
Following oral administration of capecitabine 7 days before surgery in patients with 
colorectal cancer, the median ratio of 5-FU concentration in colorectal tumors to 
adjacent tissues was 2.9 (range from 0.9 to 8.0). These ratios have not been  
compared to 5-FU infusion.
3.1.5
Human Pharmacokinetics: 
The pharmacokinetics of capecitabine and its metabolites have been evaluated in 
about 200 cancer patients over a dosage range of 500 to 3500 mg/m2/day. Over 
this range, the pharmacokinetics of capecitabine and its metabolite, 5’-DFCR were 
dose proportional and did not change over time. The increases in the AUCs of 
5’-DFUR and 5-FU, however, were greater than proportional to the increase in 
dose and the AUC of 5-FU was 34% higher on day 14 than on day 1. The 
elimination half-life of both parent capecitabine and 5-FU was about ¾ of an hour. 
The inter-patient variability in the Cmax and AUC of 5-FU was greater than 85%.
3.1.6 Absorption, Distribution, Metabolism and Excretion:
Capecitabine reached peak blood levels in about 1.5 hours (Tmax) with peak 5-FU 
levels occurring slightly later, at 2 hours. Food reduced both the rate and extent of 
absorption of capecitabine with mean Cmax and AUC decreased by 60% and 35%, 
respectively. The Cmax and AUC(0-infinity) of 5-FU were also reduced by food by 
43% and 21%, respectively. Food delayed Tmax of both parent and 5-FU by 1.5 
hours. Plasma protein binding of capecitabine and its metabolites is less than 60% 
and is not concentration-dependent. Capecitabine was primarily bound to human 
albumin (approximately 35%). Capecitabine is extensively metabolized 
enzymatically to 5-FU. The enzyme dihydropyrimidine dehydrogenase 
hydrogenates 5-FU, the product of capecitabine metabolism, to the much less toxic 
5-fluoro-5, 6-dihydro-fluorouracil (FUH2). Dihydropyrimidinase cleaves the 
pyrimidine ring to yield 5-fluoro-beta-ureido-propionic acid (FUPA). 
Finally, beta-ureido-propionase cleaves FUPA to alpha-fluoro-beta-alanine (FBAL) 
which is cleared in the urine. Capecitabine and its metabolites are predominantly 
excreted in urine; 95.5% of administered capecitabine dose is recovered in urine. 
Fecal excretion is minimal (2.6%). The major metabolite excreted in urine is FBAL 
which represents 57% of the administered dose. About 3% of the administered 
dose is excreted in urine as unchanged drug.
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3.1.7 Capecitabine Drug-Drug Interactions:WARNING
3.1.7.1
Coumarin (Coumadin):
Concurrent use of coumadin other than low dose (1 mg) coumadin 
used for line patency is contraindicated.  Patients on coumadin 
must be changed to Lovenox at least 1 week prior to starting 
capecitabine.  
Altered coagulation parameters and/or bleeding, including death, have 
been reported in patients taking capecitabine concomitantly with 
coumarin-derivative anticoagulants such as warfarin and 
phenprocoumon. These events occurred within several days and up to 
several months after initiating capecitabine therapy and, in a few cases, 
within one month after stopping capecitabine and occurred in patients 
with and without liver metastases. In a drug interaction study with single 
dose warfarin administration, there was a significant increase in the mean 
AUC of S-warfarin. The maximum observed INR value increased by 91%. 
This interaction is probably due to an inhibition of cytochrome P450 2C9 
by capecitabine and/or its metabolites.  
3.1.7.2
Phenytoin
Increased phenytoin plasma concentrations have been reported during 
concomitant use of capecitabine with phenytoin, suggesting a potential 
interaction.  Patients taking phenytoin concomitantly with capecitabine 
should be regularly monitored (e.g. weekly phenytoin and albumin levels) 
for increased phenytoin plasma concentrations and associated clinical 
symptoms.
3.1.8 Clinical Studies
 
Colorectal Cancer
The efficacy and safety of three capecitabine dosing schedules, when 
administered as first-line treatment, was evaluated in 109 patients with advanced 
colorectal cancer.  The three dosing schedules were as follows: capecitabine 2510 
mg/m2/day intermittent (2 weeks with treatment, 1 week without treatment), 
capecitabine 1657 mg/m2/day intermittent in combination with leucovorin 60 
mg/day, capecitabine 1331 mg/m2/day continuous (no rest period).  Overall 
response rates were 24%, 23% and 21% in the three groups, respectively.  
Thirteen percent of the patients discontinued treatment due to treatment-related 
adverse events (79).
Two large randomized phase III studies evaluated further the efficacy of 
capecitabine as first line treatment in metastatic colorectal cancer.  Capecitabine 
was administered at a dose of 2500 mg/m2/day, and was compared with standard 
treatment (5-FU at a dose of 425 mg/m2 in combination with leucovorin 20 mg/m2 
days 1-5 every 4 weeks).   In the North American trial, 24.8% in the capecitabine 
group had a response, compared with 15.5% in the 5-FU/leucovorin group 
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(p=0.005).  Related serious adverse events and the rate of hospitalizations was 
significantly lower (p<0.05) in the capecitabine group (80).  The European study 
demonstrated responses in 18.9% of capecitabine patients and 15.0% of the 
5-FU/leucovorin patients (16.1%).  Capecitabine resulted in significantly lower 
incidences of stomatitis, alopecia and grade 3-4 neutropenia, but a higher 
incidence of hand-foot syndrome (81).
A recent phase III trial on adjuvant therapy for stage III colon cancer showed that 
capecitabine (1,250 mg/m
2 PO BID on days 1-14 for 21 days) gave equivalent 
disease-free survival as bolus 5-FU/leukovorin, with a trend towards improved 
disease-free survival and overall survival, as well as decreased neutropenia and 
stomatitis (77).   Capecitabine is well tolerated with radiotherapy based on data 
from a phase I dose escalation trial in patients with rectal cancer [16]. Capecitabine 
was administered continuously (7 days per week) throughout a 38-day course of 
radiotherapy (50.4 Gy in 28 fractions).  The dose limiting toxicity was hand foot 
syndrome, and there was significantly less gastrointestinal and hematologic toxicity 
than expected from infusional 5-FU (78).  At M.D. Anderson, capecitabine has 
been studied in a phase II trial in patients with rectal cancer treated with 
neoadjuvant therapy.  Our results indicate that the therapy is very well tolerated 
and the treatment effect is comparable to 5-FU (15).  No randomized data currently 
exists comparing concurrent capecitabine and radiotherapy with concurrent 
continuous infusion 5-FU and radiotherapy for rectal cancer.  However, since the 
X-ACT trial showed that capecitabine is at least equivalent to 5FU/ and leucovorin 
for the adjuvant treatment of colon cancer, concurrent capecitabine and 
radiotherapy has been accepted as standard of care for preoperative treatment of 
rectal cancer at many institutions, including M.D. Anderson.  
For more than 7 years now, at M.D. Anderson, capecitabine has been typically 
given at a dose of 825 mg/m
2, Monday to Friday, concurrently with radiotherapy for 
preoperative treatment of rectal cancer.
Adverse Reactions
A total of 596 patients with metastatic colorectal cancer were treated with 1250 
mg/m
2 twice a day of capecitabine administered for 2 weeks followed by a 1-week 
rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo 
regimen (20 mg/m
2 leucovorin IV followed by 425 mg/m
2 IV bolus 5-FU, on days 
1-5, every 28 days). In the pooled colorectal database the median duration of 
treatment was 139 days for capecitabine-treated patients and 140 days for 
5-FU/LV treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 
5-FU/LV-treated patients, respectively, discontinued treatment because of adverse 
events/intercurrent illness. A total of 82 deaths due to all causes occurred either on 
study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to  
capecitabine and 32 (5.4%) randomized to 5-FU/LV.
3.1.9 Special Populations:
A population analysis of pooled data from the two large controlled studies in 
patients with colorectal cancer (n=505) who were administered Capecitabine at 
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1250 mg/m2 twice a day indicated that gender (202 females and 303 males) and 
race (455 white/caucasian patients, 22 black patients, and 28 patients of other 
race) have no influence on the pharmacokinetics of 5'-DFUR, 5-FU and FBAL. Age 
has no significant influence on the pharmacokinetics of 5'-DFUR and 5-FU over the 
range of 27 to 86 years. A 20% increase in age results in a 15% increase in AUC 
of FBAL.
3.2.9.1 Hepatic Insufficiency: 
Capecitabine has been evaluated in 13 patients with mild to moderate 
hepatic dysfunction due to liver metastases defined by a composite score 
including bilirubin, AST/ALT and alkaline phosphatase following a single 
1255 mg/m
2 dose of capecitabine. Both AUC(0-infinity) and Cmax of 
capecitabine increased by 60% in patients with hepatic dysfunction 
compared to patients with normal hepatic function (n=14). The 
AUC(0-infinity) and Cmax  of 5-FU was not affected. In patients with mild to 
moderate hepatic dysfunction due to liver metastases, caution should be 
exercised when capecitabine  is administered. The effect of severe 
hepatic dysfunction on capecitabine  is not known .
3.2.9.2 Renal Insufficiency: 
Capecitabine is contraindicated in patients with severe renal impairment 
(creatinine clearance below 30 mL/min [Cockroft and Gault]).  In patients 
with moderate renal impairment (creatinine clearance 30-50 mL/min 
[Cockroft and Gault]) at baseline, a dose reduction to 75% of the 
Capecitabine starting dose is recommended. In patients with mild renal 
impairment (creatinine clearance 51-80 mL/min) no adjustment in starting 
dose is recommended. 
Cockroft and Gault Equation:
                                                           
(140 - age [yrs]) (body wt [kg])
Creatinine clearance for males = —————————————
                                                         
(72) (serum creatinine [mg/dL])
Creatinine clearance for females = 0.85 x male value 
Following oral administration of 1250 mg/m
2  capecitabine twice a day to 
cancer patients with varying degrees of renal impairment, patients with 
moderate (creatinine clearance = 30-50 mL/min) and severe (creatinine 
clearance <30 mL/min) renal impairment showed 85% and 258% higher 
systemic exposure to FBAL on day 1 compared to normal renal function 
patients (creatinine clearance >80 mL/min). Systemic exposure to 
5’-DFUR was 42% and 71% greater in moderately and severely renal 
impaired patients, respectively, than in normal patients. Systemic 
exposure to capecitabine was about 25% greater in both moderately and 
severely renal impaired patients.
3.2.9.3
Hand-Foot Syndrome: Hand-foot syndrome (palmar-plantar 
erythrodysesthesia or chemotherapy induced acral erythema) is a 
cutaneous toxicity (median time to onset of 79 days, range from 11 to 360 
days) with a severity range of grades 1 to 3. Grade 1 is characterized by 
any of the following: numbness, dysesthesia/paresthesia, tingling, 
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painless swelling or erythema of the hands and/or feet and/or discomfort 
which does not disrupt normal activities. Grade 2 hand-and-foot 
syndrome is defined as painful erythema and swelling of the hands and/or 
feet and/or discomfort affecting the patient’s activities of daily living. 
Grade 3 hand-and-foot syndrome is defined as moist desquamation, 
ulceration, blistering or severe pain of the hands and/or feet and/or 
severe discomfort that causes the patient to be unable to work or perform 
activities of daily living. If grade 2 or 3 hand-and-foot syndrome occurs, 
administration of  capecitabine should be interrupted until the event 
resolves or decreases in intensity to grade 1. Following grade 3 
hand-and-foot syndrome, subsequent doses of  capecitabine should be 
decreased.
3.2.9.4 Cardiotoxicity: The cardiotoxicity observed with  capecitabine includes 
myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, 
cardiac failure, sudden death, electrocardiographic changes, and 
cardiomyopathy. These adverse events may be more common in patients 
with a prior history of coronary artery disease.
3.2.9.5 Hepatic Insufficiency: Patients with mild to moderate hepatic dysfunction 
due to liver metastases should be carefully monitored when  capecitabine 
is administered. The effect of severe hepatic dysfunction on the 
disposition of  capecitabine is not known.
3.3 Curcumin
3.3.1
Description
Curcumin (Diferuloylmethane) is a naturally occuring polyphenol, the active 
ingredient in the dried ground rhizome of the perennial herb Curcuma longa, 
commonly known as turmeric.  Turmeric has universal appeal as a colouring agent, 
food preservative and flavouring agent in foods.  Over the past three decades, it 
has been studied as an antioxidant, anti-inflammatory, cancer chemopreventive 
and potentially as a chemotherapeutic agent.   
The chemical name for curcumin is [1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6- 
heptadiene-3,5-dione].  This bis-unsaturated-diketone exists in equilibrium with its 
enol tautomer.  Curcumin has a molecular weight of 368.37 and the following 
structural formula:
OH
O
O
OCH3
CH3O
HO
OH
O
O
OCH3
CH3O
HO
Curcumin is an orange-yellow crystalline powder that is insoluble in water but 
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soluble in acetone, alcohol and glacial acetic acid.
Drug Formulation, Packaging, and Storage
Curcumin is available as 1 gm capsules of C3Complex (Sabinsa Corporation, New 
Jersey). This consists of standardized extract of phenolic compounds from turmeric 
root (Curcuma longa fam. Zingiberaceae) containing high purity curcuminoids 
(minimum 95% by HPLC).  Curcuminoids include 2.5-6.5% 
bisdemethoxy-curcumin, 15-25% demethoxy- curcumin, and 70-80% curcumin. 
Curcuma longa is listed in the FDA’ GRAS list, a list of food additives which are 
“Generally Recognized As Safe” by a consensus of scientific opinion. The GRAS 
list appears in the Code of Federal Regulations (CFR) Title 21 Parts 172, 182, 184 
and 186.  C3Complex should be stored at room temperature 25º C (77º F) 
[excursions permitted to 15-30º C (59-86º F] in the container in which they are 
provided.
3.3.2
Adverse Events
Incidence rates of adverse events associated with curcumin are rare. The following 
events may be expected with the administration of curcumin: 
3.3.3.1
Gastrointestinal:  Occasional mild diarrhea has been noted in some 
human subjects .
3.3.3.2
Hematologic:  None expected.
3.3.3.3
Hepatic: None expected
3.3.3.4
Renal: None expected
3.3.3.5
Respiratory: None expected
3.3.3.6
Anaphylactic-like reactions:.  No cases of anaphylactic reactions and/or 
angioedema have been reported in patients receiving curcumin.
3.3.3.7
Neurological: None expected
3.3.3.8
General: None expected
3.3.3
Drug Interactions:  None known.
3.3.4
Contraindications: Curcumin is contraindicated in patients with hypersensitivities 
to curcumin.
3.3.5
Clinical studies:
In an early report from 1987, Kuttan reported on turmeric as a topical treatment for 
oral cancers and leukoplakia (82). This research group reported a reduction in the 
size of the lesions in 10% of the 62 patients treated. The study was limited by the 
lack of a control group, no assessment of anti-inflammatory activity and no 
chemical analysis of the preparation applied. Nonetheless, the results suggest the 
potential for antineoplastic properties.
A phase I trial evaluated the pharmacokinetics of curcumin in Taiwanese subjects 
with a variety of “high risk or pre-malignant” lesions such as oral leukoplakia and 
cervical intraepithelial neoplasia among others (83). The starting oral dose was 
500 mg a day and this was escalated to 12,000 mg. No treatment related toxicity 
was observed. There was a dose related increase in measured plasma levels. Of 
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the seven patients with leukoplakia, 2 showed histologic improvement, although 
progression was observed in one. In total, 7 of 25 patients enrolled showed some 
degree of histologic improvement.  
A recent phase 1 study evaluated a curcuminoid formulation in healthy volunteers 
using a single dose of standardized powder extract, uniformly milled curcumin.  
Doses were escalated from 0.5 to 12 gm and only minimal toxicity was noted and it 
did not appear to dose-related.  The observed adverse events included diarrhea, 
headache, rash, and yellow stool.  Low levels of curcumin were detected in the 
serum in 2 subjects who received >8gm (84).  
A phase I study was completed at the University of Leicester in England using 15 
subjects with advanced colorectal cancers (85, 86). The subjects orally consumed 
curcumin doses of 450 mg up to 3.6 gm daily for up to 4 months. Two patients 
experienced mild diarrhea, but there was no dose limiting toxicity observed. Three 
indices of potential pharmacological activity of curcumin were evaluated (based on 
preclinical data). These were GST activity, levels of a deoxyguanosine adduct 
(M1G) (which is related to oxidative stress and can be altered by curcumin in the 
diet of animals or human subjects), and prostaglandin levels as an indicator of 
COX-2 activity. Curcumin consumed at 3.6 gm levels generated detectable levels 
of parent compound and conjugates in plasma and urine, demonstrating 
bioavailability outside the gastrointestinal tract. The same dose caused inhibition of 
PGE2 production in blood leukocytes (measured ex vivo). Therefore the authors 
concluded that 3.6 gm was a suitable oral dose for evaluation of phase II trials. In 
addition, since the measurement of compliance is important in the context of 
intervention trials, the consistent presence of curcumin and its conjugates in urine 
observed in patients consuming 3.6 gm of curcumin daily is of potential relevance 
to the use of curcumin as a chemopreventive agent.
In another study evaluating human pharmacokinetics, twelve patients with 
confirmed colorectal cancer received oral curcumin at 0.45, 1.8 or 3.6 gm per diem 
for 7 days prior to surgery (87). Levels of agent-derived species were determined 
in the peripheral circulation and in colorectal tissue obtained at the time of surgical 
resection. The concentrations of curcumin in normal and malignant colorectal 
tissue of patients consuming 3.6 g daily of curcumin were 12.7 ± 5.7 and 7.7 ± 1.8 
nmol/gm tissue, respectively. Curcumin sulphate and curcumin glucuronide were 
identified in the intestinal tissues of these patients. Trace levels of curcumin were 
found in the peripheral circulation. Compatible with the preclinical data presented 
above, these results also suggest that a daily dose of 3.6 gm curcumin achieves 
relatively high levels in colorectal tissue with measurable distribution of the parent 
drug outside the gut.
3.3.6 Dose Modification: The NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 will be used to score drug toxicity. If attributable toxicities are 
encountered, the drug dosage will be modified according to the following schedule 
(The drug may be restarted when the toxicity subsides to grade < 1, but missed 
doses will not be made up.) 
Please note that for any event which is apparent at baseline, the dose modification 
will apply according to the corresponding shift in toxicity grade if the investigator 
feels it is appropriate (e.g. if a patient has grade 1 asthenia at baseline which 
increases to grade 2 during treatment, this will be considered as a shift of 1 grade 
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and treated as a grade 1 toxicity for dose modification purposes).
Drug dose
Toxicity grade
Drug dose modification
4 gm twice daily
0 - 1
Continue 4 gm twice daily
2
Hold until toxicity is grade 2, then resume at 2 gm 
twice daily
3 - 4
Discontinue
The drug should be discontinued if toxicity of  < Grade 1 is not reached within 4 
weeks.
4.0 Patient Eligibility
4.1  Inclusion Criteria
4.1.1. All patients must have clinical stage T3,4 N0,1,2 or T2N1,2 adenocarcinoma of the 
rectum.  Patients will be clinically staged using endorectal ultrasound, pelvic CT or 
MRI, and physical examination.
4.1.2
Histology must be confirmed with review by the Department of Pathology at 
MDACC.
4.1.3
All patients must have no distant metastatic disease in the liver, peritoneum, lungs, 
or paraaortic lymph nodes.
4.1.4
Patients must have a performance status (Karnofsky scale) of 70% or 
greater.
4.1.5
Patients must be >/= 18 years of age.
4.1.6
Patients must have ANC > 1200 cells/mm3, platelets > 100,000/mm3, total serum 
bilirubin < 2 mg/dl, BUN <30 mg/dl, creatinine < 1.5 mg/dl or creatinine clearance > 
50cc/min (estimated as calculated with Cockcroft-Gault equation). 
Creatinine Clearance (men) = {(140 - age) x lean body weight (in kg.)}/ {Plasma 
creatinine (mg/dl) x 72} 
         Creatinine Clearance (women) = 0.85 x {(140 - age) x lean body weight (in kg.)}/
         {Plasma creatinine (mg/dl) x 72} 
4.1.7
Patients must have signed informed consent indicating that they are aware of the 
investigational nature of the study, and are aware that participation is voluntary. 
Patients must also agree to refrain from use of additional herbal supplements 
during the course of the study.  
4.1.8
Postmenopausal woman must have been amenorrheic for at least 12 months to be 
considered of non-childbearing potential.  Patients will agree to continue 
contraception for 30 days from the date of the last study drug administration. 
Sexually active males must practice contraception during the study. 
4.2  Exclusion Criteria
4.2.1
Prior complete course up to 5 Gy of radiotherapy to the pelvis.
4.2.2
Pregnant or lactating woman. Women of childbearing potential who have not 
undergone a hysterectomy with either a positive or no pregnancy test at baseline. 
Women / men of childbearing potential not using a reliable and appropriate 
contraceptive method (oral, injectable, or implantable hormonal contraceptive; 
tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or 
vasectomized partner). 
4.2.3
Treatment for other carcinomas within the last five years, except cured 
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non-melanoma skin and treated in-situ cervical cancer.
4.2.4
Patients with uncontrolled intercurrent illness including, but not limited to, ongoing 
or requiring IV antibiotics0, cardiac disease NYHA class III or IV, unstable angina 
pectoris, unstable cardiac arrythmia or tachycardia (heart rate > 100 beats/minute),  
or psychiatric illness/ social situations that would limit compliance with the study 
requirements are excluded.
4.2.5
Other serious uncontrolled medical conditions that the investigator feels might 
compromise study participation.
4.2.6
Major surgery within 4 weeks of the start of study treatment.
4.2.7
Prior unanticipated severe reaction to fluoropyrimidine therapy or known 
hypersensitivity to 5–fluorouracil or capecitabine or curcumin.
4.2.8
Concurrent use of coumadin other than low dose (1 mg) coumadin used for line 
patency.  Patients on coumadin must be changed to Lovenox at least 1 week prior 
to starting capecitabine.  
4.2.9
Concurrent use of cimetidine, allopurinol, or aluminium hydroxide and magnesium 
hydroxide-containing antacids such as Maalox.
4.2.10 Sorivudine and brivudine use within 4 weeks of the start of study treatment.
4.3
Prohibited Medications
Aluminum hydroxide- and magnesium hydroxide-containing antacids such as Maalox 
should not be used during this study because they increase the AUC and Cmax of 
capecitabine. Because clinically significant increases in prothrombin time (PT) and INR in 
patients who were stabilized on anticoagulants have been shown, patients on Coumadin® 
must be changed to Lovenox® at least 1 week prior to starting capecitabine. Low dose (1 
mg) Coumadin® is allowed. Patients on phenytoin must have their phenytoin and albumin 
levels checked weekly during chemoradiation. Vaccination with live vaccines should not 
be instituted during treatment with capecitabine.
5.0 Treatment Plan
5.1  Schema
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5.2 Radiation Therapy (Patients can elect to receive XRT treatments only at MDACC  
satellite 
radiation centers.  However, all patients must return to MDACC for evaluations 
during 
chemoradiation as required by the protocol.)
5.2.1   Simulation will be done using a CT-simulator.
5.2.2
Equipment: Megavoltage photons will be used to deliver radiotherapy.  
5.2.3
Target Volumes:
5.2.3.1
Gross tumor volume (GTV): The GTV will comprise the pre-operative 
tumor volume and any involved lymph nodes, as defined by pre-operative 
CT scans and/or colonoscopy.
5.2.3.2
Clinical target volume 1 (CTV1): The CTV for the initial course of 
radiotherapy will comprise the GTV, the perirectal nodes, the presacral 
nodes and the internal iliac nodes.  The external iliac nodes may also be 
included, at the discretion of the treating radiation oncologist.
5.2.3.3
Clinical target volume 2 (CTV2): The CTV for the boost will comprise the 
GTV.
5.2.3.4  Typical field design: A three-field technique (posteroanterior, right and left 
lateral fields) will be used to administer pelvic radiotherapy (to CTV1) with 
the patient on a belly board.  Pelvic fields will extend from the L5–S1 
interspace to the bottom of the obturator foramen or 3 cm below the 
tumor, whichever was lower.Laterally the field will extend 2 cm lateral to 
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the bony pelvis at its widest point. The anterior border of the lateral 
fields will be individually shaped to encompass the common iliac and 
internal iliac nodes for all tumors and the external iliac nodes for T4 
tumors invading the vagina, prostate, or urinary bladder. The posterior 
border will 
include the entire sacrum with a 1-cm margin posteriorly. 
Fields will initially be dosimetrically weighted 2 (posteroanterior portal): 1 
(right lateral portal): 1 (left lateral portal), usually with 45° wedges on the 
lateral fields 
and adjusted to ensure adequate coverage and 
homogeneity. The boost will be delivered using opposed lateral fields 
targeting CTV2 with a margin of 2-3 cm circumferentially and with 
inclusion of the presacral space and sacrum in the field.
5.2.4
Dose: CTV1 will be treated to a dose of 45 Gy. This will be followed by a boost to 
CTV2 with a dose of 5.4 Gy. At the discretion of the treating radiation oncologist, 
up to an additional 3.6 Gy may be administered during the boost. All plans will be 
generated using 3D conformal techniques. At the discretion of the radiation 
oncologist, an intensity-modulated radiation therapy (IMRT) plan may be 
generated.
5.2.5
Fractionation:  Radiotherapy will be delivered in 180 cGy once daily fractions for 28 
fractions.
5.2.6
Dose constraints:  Dose to the femoral heads will be limited to 50 Gy.  The volume 
of small bowel getting > 45 Gy will be minimized.  Dose heterogeneity will be less 
than 10%.
5.2.7
Radiotherapy will be interrupted for treatment related > Grade 2 non-hematological 
toxicity until it resolves to grade 1, then continued.  If radiotherapy is interrupted, 
then capecitabine will also be interrupted. Please note that for any event which is 
apparent at baseline, the interrruption will apply according to the corresponding 
shift in toxicity grade if the investigator feels it is appropriate (e.g. if a patient has 
grade 1 asthenia at baseline which increases to grade 2 during treatment, this will 
be considered as a shift of 1 grade and treated as a grade 1 toxicity for radiation 
interruption purposes).
5.3
Chemotherapy
5.3.1 Capecitabine
Capecitabine will be given at 825 mg/m
2 PO BID only on days of radiation (Monday 
through Friday). Dose adjustment of capecitabine will be made as needed (see 
5.3.1.3).
5.3.1.1 Cautions when used with other medications
5.3.1.1.1
Concurrent use of coumadin other than low dose (1 mg) coumadin 
used for line patency is contraindicated.  Patients on coumadin 
must be changed to Lovenox at least 1 week prior to starting 
capecitabine.  
5.3.1.1.2
Increased phenytoin plasma concentrations have been reported 
during concomitant use of Capecitabine with phenytoin, 
suggesting a potential interaction. Patients taking phenytoin 
concomitantly with Capecitabine should be monitored weekly for 
increased phenytoin plasma concentrations and associated 
clinical symptoms.
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5.3.1.1.3
Allopurinol.  Oxypurinol, a metabolite of allopurinol, can potentially 
interfere with 5-FU anabolism via orotate 
phosphoribosyltransferase.  Although this was originally used as a 
strategy to protect normal tissues from 5-FU-associated toxicity, 
further laboratory studies suggested possible antagonism of the 
anticancer activity of 5-FU in some tumor models.  If a patient is 
receiving allopurinol, the need for taking this medicine should be 
ascertained.  If possible, allopurinol should be discontinued prior 
to starting on this regimen, and another agent substituted for it.
5.3.1.1.4
Cimetidine: Because cimetidine can decrease the clearance of 
5-FU, patients should not enter on this study until the cimetidine is 
discontinued.  Ranitidine or a drug from another anti-ulcer class 
can be substituted for cimetidine if necessary. 
5.3.1.1.5 Sorivudine and Brivudine: A metabolite of the above two 
investigational antiviral agents, 5-bromovinyluracil, is a potent 
inhibitor of dihydropyrimidine dehydrogenase, the enzyme that 
catabolizes 5-FU.  Patients should not receive concurrent therapy 
with either of these antiviral agents while receiving capecitabine.  
If a patient has received prior sorivudine or brivudine, then at least 
four weeks must elapse before the patient receives capecitabine 
therapy.
5.3.1.2   Dosing
Capecitabine should be given approximately 12 hours apart (morning and 
evening), and taken within 30 minutes after the ingestion of food with 
approximately 200 mls of water (not fruit juices).
5.3.1.3   Dose modification guidelines of Capecitabine
Dose Modifications: 
For any event which is apparent at baseline, the dose modifications will apply 
according to the corresponding shift in toxicity grade if the investigator feels it is 
appropriate (e.g. if a patient has grade 1 asthenia at baseline which increases to grade 
2 during treatment, this will be considered as a shift of 1 grade and treated as a grade 
1 toxicity for dose modification purposes).
Capecitabine treatment interruptions are regarded as lost treatment days and missed doses 
should not be replaced; the planned treatment schedule should be maintained.  
Once a dose has been reduced it should not be increased at a later time.
Toxicity
NCI Grade (a) (Value)
Neutropenia
Capecitabine will be held  for >grade 2 neutropenia. Capecitabine can be restarted at 75% of 
the dose after recovery of neutropenia to grade 1. Patients will be removed from the study if 
they do not recover from the neutropenia.
Neutropenic fever
(grade 4 neutropenia and  grade 2 fever) Interrupt capecitabine until resolved to grade 0, then 
continue at 75% of starting dose. Patients will be removed from the study if they do not 
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recover from the neutropenic fever.
Other hematological toxicities
No dose reductions or interruptions will be required for anemia as it can be satisfactorily 
managed by  transfusions, if necessary.
Diarrhea  [all; stools/day > pretreatment]
1          (2-3 stools/day)      :      Maintain dose
2        (4-6 stools/day)Interrupt until grade 0-1, continue according to number of appearances               
1st                  :      75% of starting dose.
                    2nd                 :      50% of starting dose.
                    3rd                  :      50% of starting dose. 
3          (7-9 stools/day)Interrupt until grade 0-1, continue according to number of appearances 
                    1st                  :      75% of starting dose.
                    2nd                 :      50% of starting dose.
                    3rd                  :      50% of starting dose. 
4          (10 stools/day)Interrupt until grade 0-1, then continue at 50% of starting dose. 
Hand-Foot Syndrome 
1          Maintain dose
2          Interrupt until grade 0-1, then continue at 75% of starting dose.
3          Interrupt until grade 0-1, then continue at 50% of starting dose.
4          (not applicable)
Other non-hematological toxicity 
For toxicities which are considered by the Investigator unlikely to develop into serious or 
life–threatening events and which do not result in a delay or interruption of therapy (e.g. 
alopecia, altered taste etc.), treatment will be continued at the same dose without reduction or 
interruption.
1          Maintain dose
2          Interrupt until grade 0-1, continue according to number of appearances of same 
toxicity 
                    1st                  :      75% of starting dose.
                    2nd                 :      50% of starting dose.
                    3rd                  :      50% of starting dose. 
3          Interrupt until grade 0-1, continue according to number of appearances of same 
toxicity 
                    1st                  :      75% of starting dose.
                    2nd                 :      50% of starting dose.
                    3rd                  :      50% of starting dose. 
4          Interrupt until grade 0-1, then continue at 50% of starting dose. 
a.
National Cancer Institute Common Toxicity Criteria Version 3.0, see Appendix B.
5.3.1.4 Special Instructions Regarding Treatment of Toxicity;
5.3.1.4.1 Grade 2/3 Hand–Foot Skin Reaction
Treat symptomatically (recommended use of emollients).  
The use of vitamin B6 Pyridoxine has been reported to be of possible 
benefit and is permitted for symptomatic or secondary prophylactic 
treatment of hand-foot skin reaction. 
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5.3.1.4.2 Neutropenia
When the ANC has recovered to 1,500/mm
3 and fever or infection has 
resolved, the patient may restart treatment, with capecitabine at 75% 
of the starting dose if the patient had > grade 2 neutropenia, and at 
100% of the starting dose if the patient did not have > grade 2 
neutropenia.
5.3.1.4.3    Diarrhea 
A three-step plan to manage diarrhea will be used. The goal will be to 
keep the frequency of bowel movements to less than four per day. 
Patients will initially take Lomotil as needed. When  that is no longer 
sufficient to control the increased frequency of bowel movement, 
patients take 2 lomotil every 3-4 hours, which is step 2. Subsequently, 
Imodium is added and alternated with Lomotil, which is step 3; 2 
tablets of one or the other is taken every 2-3 hours. Delayed and 
immediate release narcotics will be used at the discretion of the 
treating physician. Infectious diarrhea must be considered as an 
etiology, particularly if diarrhea occurs during the first two weeks of 
radiation.  Outpatient intravenous rehydration will be given in patients 
who become dehydrated. At the discretion of the treating physician, 
empiric use of a fluoroquinolone may be considered.
5.3.1.5  Warnings and Precautions
5.3.1.5.1
Renal Insufficiency: Patients with moderate renal impairment at 
baseline require dose reduction (See section 3.2.9.2, Dosage 
Regimen and Administration.) Patients with mild and moderate renal 
impairment at baseline should be carefully monitored for adverse 
events. Prompt interruption of therapy with subsequent dose 
adjustments will be made if a patient develops a grade 2 to 4 adverse 
event.  patients will be taken off study if they do not recover. 
Capecitabine is contraindicated in patients with a creatinine clearance 
of < 30 ml/min. 
5.3.1.5.2 Pregnancy/Nursing: Capecitabine may cause fetal harm when given 
to a pregnant woman. If the drug is used during pregnancy, or if the 
patient becomes pregnant while receiving this drug, the patient should 
be apprised of the potential hazard to the fetus. Women of 
childbearing potential should be advised to avoid becoming pregnant 
while receiving treatment with capecitabine. Because of the potential 
for serious adverse reactions in nursing infants from capecitabine, it is 
recommended that nursing be discontinued when receiving 
capecitabine therapy.
5.3.1.5.3
Coagulopathy: Patients receiving concomitant capecitabine and oral 
coumarin-derivative anticoagulant therapy should have their 
anticoagulant response (INR or prothrombin time) monitored 
frequently in order to adjust the anticoagulant dose accordingly. A 
clinically important Capecitabine-Warfarin drug interaction was 
demonstrated in a clinical pharmacology trial. Altered coagulation 
parameters and/or bleeding, including death, have been reported in 
patients taking capecitabine concomitantly with coumarin-derivative 
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anticoagulants such as warfarin and phenprocoumon. Postmarketing 
reports have shown clinically significant increases in prothrombin time 
(PT) and INR in patients who were stabilized on anticoagulants at the 
time capecitabine was introduced. These events occurred within 
several days and up to several months after initiating capecitabine 
therapy and, in a few cases, within one month after stopping 
capecitabine. These events occurred in patients with and without liver 
metastases. Age greater than 60 and a diagnosis of cancer 
independently predispose patients to an increased risk of 
coagulopathy.  
5.3.1.5.4 Cardiotoxicity: The cardiotoxicity observed with capecitabine includes 
myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, 
cardiac failure, sudden death, electrocardiographic changes, and 
cardiomyopathy.  These adverse events may be more common in 
patients with a prior history of coronary artery disease. 
5.3.1.5.5
General: This treatment is foreseen as a self-administered out-patient 
treatment, and in certain circumstances adverse events that could 
occur, such as diarrhea, or hand-foot syndrome can rapidly become 
serious. In the case where a patient experiences any toxicity between 
scheduled visits, the patient will be instructed to contact the clinic as 
soon as possible, for further directions, discontinuation of study 
medication, and/or treatment.
5.4
Curcumin or Placebo
Curcumin or placebo capsules will be given at  4 gm PO twice daily on an empty stomach 
throughout the chemoradiation therapy period and for six additional weeks.  On days of 
radiation therapy, the capsules will be consumed approximately 1 hour before radiation 
therapy.  On the day that blood is drawn for pharmacology of curcumin or placebo, the 1 
hour interval between capsules and radiation may be prolonged (see 7.5). Whenever 
capecitabine is discontinued, curcumin or placebo will be discontinued as well.
5.5
Patient Monitoring and Supportive Care
Patients will be evaluated weekly by clinicians participating in their care. The clinician will 
be responsible for performing a history, physical exam, and monitoring lab work.  The 
common acute effects of chemoradiation are managed with aggressive outpatient 
supportive care. The judicious use of prophylactic antiemetics and a three-step plan to 
manage diarrhea are used. The goal is to keep the frequency of bowel movements to less 
than four per day. Patients are initially instructed to take Lomotil as needed. When that is 
no longer sufficient to control the increased frequency of bowel movement, patients take 2 
lomotil every 3-4 hours, which is step 2. Subsequently, Imodium is added and alternated 
with Lomotil, which is step 3; 2 tablets of one or the other is taken every 2-3 hours. 
Delayed and immediate release narcotics are used regularly.  Another common acute 
reaction is desquamation of the perineal skin and genitalia, which usually occurs with 
irradiation of low rectal lesions.  These reactions can be effectively managed with a 
lanolin-containing barrier cream used in the perianal area, anusol suppositories for anal 
canal pain, and Aquaphor for the anterior skin reactions. Moist desquamation often 
requires narcotic pain medication, sitz baths, and the use of a hydrogel dressing (Vigilon 
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or Cool Magic).   
5.6 Surgery and Adjuvant Therapy
Patients will be evaluated by a surgeon 6-12 weeks after completion of radiotherapy for 
consideration of surgery.  A separate consent form will be obtained for surgery.  Further 
systemic therapy may be offered at the discretion of the treating oncologist.
6.0 Pretreatment evaluation
6.1
Prior to Study Enrollment:  
6.1.1
Patients must have the following tests before study enrollment: 
6.1.1.1
Blood chemistries (bilirubin, alkaline phosphatase, ALT, AST, BUN, 
creatinine, phosphorus, calcium, glucose, total protein, albumin, and 
electrolytes [sodium, potassium, carbon dioxide, and chloride], Complete 
blood count (CBC: hemoglobin, hematocrit, WBC with differential blood 
cell counts (neutrophils, bands, lymphocytes, monocytes, eosinophils, 
basophils) and platelets), carcinoembryonic antigen (CEA), urinalysis, all 
within 10 days of enrollment. PT and INR will be done if patient is on 
coumadin and phenytoin levels will be checked in patients on phenytoin.
6.1.1.2
Urine pregnancy test within 72 hours of enrollment in women of 
child-bearing potential
6.1.1.3
Radiographic studies (CXR or chest CT; CT of the abdomen and pelvis) 
within 30 days of enrollment
6.1.1.4
Colonoscopy within 3 months of enrollment and flexible sigmoidoscopy/ 
EUS within 30 days of enrollment
6.1.1.5
Endoscopic biopsy prior to study enrollment
6.1.2
After consent but prior to initiating chemoradiation therapy, additional tests for 
research purposes include: 
6.1.2.1
MD Anderson symptom inventory (MDASI) questionnaire gastrointestinal 
module (appendix F)
6.1.2.2
Brief Fatigue Inventory (BFI) (appendix E)
6.1.2.3
Blood collection for cytokine analysis
7.0 Evaluation During Study
During chemoradiation therapy, the patients will be assessed as follows:
7.1
Blood chemistries (bilirubin, alkaline phosphatase, ALT, AST, BUN, creatinine, 
phosphorus, calcium, glucose, total protein, albumin, and electrolytes [sodium, potassium, 
carbon dioxide, and chloride], and complete blood count (CBC: hemoglobin, hematocrit, 
WBC with differential blood cell counts (neutrophils, bands, lymphocytes, monocytes, 
eosinophils, basophils) and platelets) every week. Phenytoin levels will be checked in 
patients on phenytoin.
7.2
Weekly port-films
7.3
Weekly MDASI-GI and BFI questionnaires
7.4
Weekly blood collection for cytokine analysis
7.5
During week 2 (after at least 5 fractions of radiation therapy) of chemoradiation therapy:
a)
Optional endoscopic biopsy
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b)
Optional blood collection for pharmacology (1 hour before and 1 hour after intake of 
curcumin or placebo)
7.6
Patients will be assessed by physician and research nurse at least once every 5 radiation 
fractions or as needed +/- 1 or 2 radiation fractions
Six-twelve weeks after chemoradiation therapy, patients will be restaged as follows:
7.9
Blood chemistries (bilirubin, alkaline phosphatase, ALT, AST, BUN, creatinine, 
phosphorus, calcium, glucose, total protein, albumin, and electrolytes [sodium, potassium, 
carbon dioxide, and chloride], complete blood count (CBC: hemoglobin, hematocrit, WBC 
with differential blood cell counts (neutrophils, bands, lymphocytes, monocytes, 
eosinophils, basophils and platelets), and CEA. 
7.10 MDASI-GI and BFI questionnaires
7.11 Blood collection for cytokine analysis
7.12 Study Calendar:
Tests &
Procedures
Pre-
treatment
During
chemo-
radiation
Week #2 of 
chemo-
radiation
6-12 weeks 
after chemo-
radiation
(restaging)
Follow-up (5)
H&P; KPS
x (1)
weekly
x
CBC (see 6.1)
x (1)
weekly
x
Serum chemistries (see 6.1)
x (1)
weekly
x
CEA
x (1)
x
Phenytoin level (patients 
on phenytoin)
x (1)
weekly
PT, INR (patients on 
coumadin)
x (1)
weekly
x
Urinalysis
x (1)
Urine pregnancy test 
(see 6.1)
x (2)
Abd-Pelvic CT 
x(3)
Flexible 
sigmoidoscopy/EUS
x (3)
Endoscopic ultrasound 
biopsy
x
x (6)
CXR
x (3)
Colonoscopy
x (4)
MDASI, BFI
x
weekly
x
x
Cytokines (see 9.2) (6)
x
weekly
x
x
Pharmacology (see 9.1) (6)
x
Telephone call (toxicity 
check)
x
(1) Within 15 days of enrollment
(2) Urine pregnancy test within 72 hours of enrollment, women of child bearing age only
(3) Within 30 days of enrollment
(4) Within 3 months of enrollment
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(5)  Telephone call 1 month +/- 1 week after last dose of curcumin/placebo.
(6) Optional
8.0 Evaluation After Treatment
After finishing chemoradiation treatments and “6 week maintenance (curcumin vs. 
placebo)”, the patient will have a telephone follow-up visit 1 month +/- 1 week.  Since 
most surgeries take place within the 1-3 weeks after the 6 week maintenance, the 
patient will typically be in surgical planning/ implementation/recovery. Furthermore, 
since most patients are from out of town, this follow-up visit is best accomplished via a 
telephone call. Therefore, toxicity check will be verbal and a note will be recorded in the 
patient’s chart. Surgical toxicity will not be recorded since it is likely that patients will 
complain of incisional discomfort, abdominal pain, and symptoms related to surgery. 
Most side effects of chemoradiation would have resolved by the time of this telephone 
call. 
Patients may receive adjuvant chemotherapy after surgery, at the discretion of the 
treating medical oncologist.
Standard-of-care follow-up evaluations will be undertaken per the directions of the 
treating medical oncologist. The patient chart will be reviewed periodically to capture 
failure and survival information.
9.0 Correlative Studies
9.1
Clinical pharmacology studies (optional)
9.1.1
Blood samples (20 ml) will be collected in lavender top tubes at the Endoscopy 
suite during the second week of CRT and processed as follows. This will be 
performed pre-dose and 1-hour +/- 10 minutes post-dose of curcumin or placebo.  
A third of the sample will be centrifuged immediately (1500 x g for 15 min at 4°C). 
The plasma is removed and stored at -20°C. The samples will be shipped in the 
frozen state for storage until ready for analysis in the core pharmacology lab.  
The remaining two-thirds of the sample will be transferred into a 50 cc conical 
tube to which is added an equal volume of PBS. The tube is inverted 10 times. 
The diluted blood is transferred to another 50 ml conical tube that contains an 
equal volume of Ficoll-Paque using a transfer pipette. The diluted blood is 
carefully laid over the Ficoll-Paque at room temperature. The tube is capped and 
centrifuged (700 x g for 30 min) at room temperature using a swinging bucket 
rotor. Cells (peripheral blood mononuclear cells, PBMC) are obtained at the 
resulting interface, transferred to another tube and washed once with PBS. After 
centrifugation, cells are then resuspended, and samples saved for 
immunocytochemical analyses.
9.1.1.1 Plasma curcumin, curcumin glucuronide, curcumin sulfate, 
demethoxycurcumin,and bisdemethoxycurcumin will be measured  using 
high-performance liquid chromatography and mass spectrometry.  
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9.1.1.2 Curcumin and its metabolites will be expressed in micrograms of drug per 
milliliter of plasma.  
9.1.1.3 Results will be expressed as means +/- standard deviations.
9.1.1.4 PBMC will be used for immunocytochemical analysis.
9.1.2
Biopsies (tumor) will be obtained during the second week of chemoradiation 
therapy and at restaging.  Surgical specimen will also be collected.
9.1.2.1 Biopsy tissue and surgical tissue will be immediately frozen in liquid 
nitrogen and stored at -80
oC.  The tissue will be homogenized (liquid 
nitrogen cooled mortar and pestle, cold spatula transfer to cooled 
eppendorf, cryocentrifuged, digested, homogenized in ultrasonic 
homogenizer) and then analyzed for targets (curcumin and its 
metabolites) as noted above.  
9.1.2.2 Curcumin and its metabolites will be expressed in micrograms of drug per 
milligram of wet tissue weight.
9.1.1.3 Results will be expressed as means +/- standard deviations.
9.2
Cytokine assays (optional)
These will be performed by personnel who are blinded to the treatment status of the patients.
9.2.1
Blood will be collected in lavendar top tubes at study initiation and weekly during 
chemoradiation for cytokine analyses.  This will be stored in the laboratory until 
bunched samples can be analyzed in the core cytokine lab. The cytokines 
assayed will include IL-1b, IL-8 and TNF-a.
9.3
Surrogate marker analyses
These will be performed by personnel who are blinded to the treatment status of the patients.
Fresh frozen tumor from biopsy and surgical specimens will be processed for correlative 
studies as noted below:
9.3.1
A portion of tumor tissue will be snap frozen for measurement of drug levels as 
noted in 9.1.2.  
9.3.2
A portion will be frozen for Western blot analysis, electrophoretic mobility shift 
assay, and microarray analysis. Tissue will be homogenized and probed with 
specific antibodies for Western blot analysis of key proteins including bcl-2, bax, 
PARP, VEGF, cyclin D1, and cox-2.  Nuclear extracts will be prepared for EMSA 
of NF-kB DNA-binding.  
9.3.3
Another portion will be processed for immunohistochemical analysis including 
p65, p-stat3, cox-2, VEGF, Ki-67, and CD31 evaluation.
9.3.4
The remainder will be frozen for further analysis.
9.3.5
Labeled sterile Nunc tubes will be used to store tissue samples.
9.3.6
All tissue not mentioned above will be routinely processed as per the pathology 
department.
10.0 Criteria for Toxicity
Patients will be evaluated each week during chemoradiation just before surgery and 1 month +/- 
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2 days after surgery by a physician and research nurse regarding  the occurrence and nature of 
any adverse events.  Appendix B provides the grades to be assigned for various types of 
toxicities.
10.1    Off-study criteria
Patients who have documented clinical progression of disease that is discovered upon 
symptomatic progression during therapy will be taken off study. Patients will be taken off 
study if they fail to complete protocol therapy for reasons other than treatment related 
toxicity or tumor progression and will not be counted in the analysis.  Patients will be 
taken off study if they miss two consecutive appointments.
10.2 
Criteria for Discontinuing Therapy 
Treatment will be discontinued if an unpredictable, irreversible toxicity 
develops, or patient chooses to discontinue treatment/study. 
10.3
See 12.0 for reporting requirements.
11.0 Data and Protocol Management
11.1
Patients will be registered by calling a Radiation Oncology Research Nurse, who will 
then register them on the MDACC computerized Clinical Oncology Research System 
(CORe).
12.0 Reporting Guidelines
12.1 All serious adverse events described in Appendix A will be reported to the IRB. 
Serious adverse events will be delivered to the Office of Research Education and 
Regulatory Management - IND office and will be submitted to the FDA by the Project 
Manager for IND safety, according to 21 CFR 312.32.
12.2
Surgical complications will not be reported.
12.3
Lymphopenia, high blood sugar and electrolyte abnormalities will not be reported.
12.4
Toxicities grade 2 and above will be captured in PDMS data.
13.0 Statistical Considerations
The Department of Biostatistics will create a randomization website to be used by the 
pharmacists to assign treatments to patients.  Patients will be randomized to control and 
experimental treatment arms in a 1:2 ratio.  That is, the probability of a patient being 
randomized to the control arm (placebo) is 1/3, while the probability of a patient being 
randomized to the experimental arm (curcumin) is 2/3. The primary outcome for this trial is the 
pCR rate, which is evaluated at the time of surgery.  We expect the pCR rate to be 18% in the 
control group (3, 5, 15).
Our target pCR rate is 36% or more in the curcumin treatment group. For those patients 
randomized to curcumin we will employ a two-stage design with a significance level of 10% and 
80% power.  We will treat 16 patients in the first stage, and if there are 3 or more patients with 
pCR among these first 16 patients, we will treat 14 additional patients in the second stage, for a 
total of 30 patients.  Curcumin will be considered for further development if there are 9 or more 
patients with pCR among these 30 patients.  The probability of stopping the study after the first 
stage if the pCR rate is 18% is 0.43, while the probability of stopping the study after the first 
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stage if the pCR rate is 36% is 0.04.  The expected sample size for this two-stage design is 24 
patients, and the actual significance level is 7.5%." and replace it with "The expected sample 
size if the pCR rate is 18% is 24, and the actual significance level is 7.5%. We will randomize 15 
patients to the placebo arm, yielding a total maximum sample size of 45 patients.  We will 
accrue patients at a rate of 4 patients per month. 
Secondary Outcomes
Downstaging
We will also compare the 2 treatment arms with respect to the proportions of patients that are 
downstaged at the time of surgery.  We expect the proportion of patients in the control arm that 
will be downstaged is 60% (3, 5, 15).  With 15 patients in the control arm and 30 patients in the 
experimental arm, we will have 82% power to detect an increase in the proportion of patients 
that are downstaged to 95%.
Correlative Studies
For the experimental treatment we will compare the concentration of curcumin in the tumor  with 
the curcumin concentration levels in serum.  We will find the difference in curcumin 
concentration levels in tumor and serum for each patient (tumor – serum), and then we will use 
a paired t-test to determine whether the mean difference is statistically significant.
For the experimental treatment we will estimate the correlation between the curcumin level in 
tumor tissue and 1) NF-kB activity, and 2) pCR.  We will also estimate the correlation between 
the curcumin level in serum and these same variables.
We will use a logistic regression model with pCR as the dependent variable to assess the 
association between pCR and NF-kB activity and treatment.
We will also compare between treatment groups changes in selected components of known 
relevant pathways in both normal and tumor tissue.  These include bcl-2, bax, PARP, VEGF, 
cyclin D1, p-stat3, Ki-67, CD31and cox-2. 
Quality of Life and Toxicity
Patients will complete validated quality of life (QoL) instruments at baseline and weekly  during 
chemoradiation. These instruments include the MD Anderson Symptom 
Inventory-Gastrointestinal (MDASI-GI) and Brief Fatigue Inventory (BFI).  A panel of cytokines 
(IL-1b, IL-8 and TNF-a) will be assayed at these same evaluation times.  We will estimate the 
correlation between the various cytokine levels and the various QoL instrument scores.
We will also compare changes from baseline in cytokine levels between treatment groups using 
a repeated measures analysis of variance model.  We will construct side-by-side boxplots of 
changes from baseline in cytokine levels by treatment group for each evaluation time.  We will 
also construct side-by-side boxplots of changes from baseline of QoL instrument scores by 
treatment group for each evaluation time.
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