Neoplasms

All Conditions

Digestive System Diseases

Carcinoma

Rectal Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Irinotecan

Fluorouracil

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Topoisomerase I Inhibitors

Enzyme Inhibitors

Radiation 45 Gy in 25 fractions to the pelvis.

5FU CIVI 225 mg/m2/day by CIVI during radiation

Surgery 6-10 weeks after completion of preoperative radiation if disease has become resectable.

Radiation 45 Gy in 25 fractions to the pelvis.

5FU CIVI 225 mg/m2/day by CIVI during radiation

Irinotecan 50 mg/m2 IV weekly for 5 doses.

Surgery 6-10 weeks after completion of preoperative radiation if disease has become resectable.

Radiation

Surgery of resectable lesions

Benjamin Tan, M.D.

Determine if genotype-directed neoadjuvant chemoradiation, using information from the thymidylate synthase promoter polymorphism, result in a greater degree of tumor downstaging in high risk patients compared to historical controls.

Genotype-directed Neoadjuvant Chemoradiation for Rectal Carcinoma

Tumor downstaging (DS) is defined as a decrease in the T stage of the primary tumor by at least 1.

Historical studies demonstrate a DS rate of 45%.

Complete tumor response is defined as the absence of any viable tumor in the rectum (ypT0).

Pathologic complete response (pCR) is defined as the absence of any viable tumor in the rectum or in the perirectal lymph nodes (ypT0N0).

pCR rate of historical controls is 8%-14%.

The questionnaire is encouraged but not required.

Washington University School of Medicine

Two patients in both the "Good Risk Arm" and the "Poor Risk Arm" withdrew consent and are not included.

Good Risk (Thymidylate Synthase (TYMS)*2/*2, *2/*3, *2/*4)

Poor Risk (Thymidylate Synthase (TYMS)*3/*3, *3/*4)

Good Risk (TYMS*2/*2, *2/*3, *2/*4)

Poor Risk (TYMS*3/*3, *3/*4)

Total

Age, Continuous

Sex: Female, Male

White

African American

Hispanic

Asian

Race/Ethnicity, Customized

United States

Region of Enrollment

*2/*2

*2/*3

*2/*4

*3/*3

*3/*4

Thymidylate Synthase Enhancer Region (TSER) genotype

Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 0 Fully active able to carry on all predisease performance without restriction

1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (light house work/office work)
2. Ambulatory, capable of all selfcare but unable to carry out any work activities. Up \& about more than 50% of waking hours
3. Capable of limited selfcare, confined to bed/chair more than 50% of waking hours
4. Completely disabled. Cannot carry on selfcare. Totally confined to bed/chair
5. Dead

Performance status

Stage IIA (T3, N0, M0)

Stage IIB (T4, N0, M0)

Stage IIIA (T1-2, N1, M0)

Stage IIIB (T3-4, N1, M0)

Stage IIIC (T-any, N2, M0)

Stage IV (T-any, N-any, M1)

* T describes how far the primary tumor has grown into the wall of the intestine and whether it has grown into nearby areas.
* N describes the extent of spread to nearby lymph nodes.
* M indicates whether the cancer has spread to other organs of the body.

Numbers or letters appear after T, N, and M to provide more details about each of these factors. The numbers 0 through 4 indicate increasing severity. The letter X means "cannot be assessed because the information is not available."

Baseline Stage

T1-2

Baseline clinical T stage

Baseline clinical N stage

Baseline clinical M stage

Endoscopic ultrasound

CT Scan +/- PET Scan

Clinical staging modality

5-10

Tumor distance from anal verge (cm)

Well differentiated

Moderately differentiated

Poorly differentiated

Not reported

Tumor grade

Benjamin R. Tan, M.D.

8 not evaluable in Good Risk arm-(1)death before surgery (1)clinical CR w/o surgery (1)refused surgery (2)not resectable (2)withdrew consent (1)delayed surgery and given FOLFOX

6 not evaluable in Poor Risk arm-(1) death prior to surgery (1)clinical CR no surgery (1)refused surgery (2)withdrew consent (1)not given irinotecan by treating physician

Rate of Tumor Downstaging Compared With Historical Controls.

ypT0

Complete Response Rates

The data was not collected for this outcome measure as the questionnaire was encouraged but not required.

Define Patient Quality of Life Prior to and Following Neoadjuvant Chemoradiation.

Determine Patient Fears and Expectations of Pharmacogenetics.

Nausea

Vomiting

Diarrhea

Dehydration

Mucositis

GI bleed

Ileitis

Enteritis

Dyspnea

Neutropenia

Anemia

Pain

Perforation

Pelvic abscess

Crohn's flare

Syncope

Rash

Fatigue

Atrial fibrillation

Infection

Headache

Small bowel obstruction

Grade 3 to 4 toxicities related to treatment and surgery using CTC Version 2.0.

Two of the patients in the Good Risk arm withdrew consent and are not included. Two of the patients in the Poor Risk arm withdrew consent and are not included.

Toxicities by Genotype Group (Good Risk Versus Poor Risk)

1 year

2 years

3 years

Overall Survival

14 patients in the Good Risk arm had metastatic rectal cancer at time of enrollment are not included in this analyses.

3 patients in the Poor Risk arm had metastatic rectal disease before surgery and are included in this analyses.

2 of the patients in the Good Risk arm and Poork Risk arm withdrew consent and are not included.

Relapse-free Survival

CC (MTHFR 677C>T)

CT (MTHFR 677C>T)

TT (MTHFR 677C>T)

Genomic DNA was isolated from whole blood using the Puregene DNA isolation kit.

MTHFR gene = methylenetetrahydrofolate reductase (NAD(P)H)

Without Grade 3-4 Diarrhea and/or Mucositis

With Grade 3-4 Diarrhea and/or Mucositis

2 of the patients in the Good Risk arm withdrew consent and are not included.

Associations Between MTHFR Genotypes and Grade 3-4 Diarrhea and/or Mucositis (Good Risk Group)

Genomic DNA was isolated from whole blood using the Puregene DNA isolation kit.

2 of the patients in the Poor Risk arm withdrew consent and are not included.

Associations Between MTHFR Genotypes and Grade 3-4 Diarrhea and/or Mucositis (Poor Risk Group)

AA (MTHFR 1298A>C)

AC (MTHFR 1298A>C)

CC (MTHFR 1298A>C)

677C-1298A

677C-1298C

677T-1298A

Associations Between MTHFR Haplotypes and Grade 3-4 Diarrhea and/or Mucositis (Good Risk Group)

Associations Between MTHFR Haplotypes and Grade 3-4 Diarrhea and/or Mucositis (Poor Risk Group)

CA-CA

CA-CC

CA-TA

CC-CC

CC-TA

CC-TC

TA-TA

Associations Between MTHFR Diplotypes and Grade 3-4 Diarrhea and/or Mucositis (Good Risk Group)

Associations Between MTHFR Diplotypes and Grade 3-4 Diarrhea and/or Mucositis (Poor Risk Group)

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Genotype-directed Neoadjuvant Chemoradiation for Rectal Carcinoma	NCT00682786	Rectal Carcinom...	5FU Radiation Surgery of rese... Irinotecan	18 Years -	Washington University School of Medicine
Genotype-directed Neoadjuvant Chemoradiation for Rectal Carcinoma	NCT00682786	Rectal Carcinom...	5FU Radiation Surgery of rese... Irinotecan	18 Years -	Washington University School of Medicine

Spots Global Cancer Trial Database for surgery of resectable lesions