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A Phase II Open- Labeled, Prospective Study to Determine the Efficacy of Pre- Operative Chemotherapy With Six Cycles of Modified FOLFOX 6 Followed by Total Mesorectal Excision (TME) Followed by an Additional Six Cycles of FOLFOX 6

Phase 2
18 Years
70 Years
Not Enrolling
Rectal Neoplasms

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Trial Information

A Phase II Open- Labeled, Prospective Study to Determine the Efficacy of Pre- Operative Chemotherapy With Six Cycles of Modified FOLFOX 6 Followed by Total Mesorectal Excision (TME) Followed by an Additional Six Cycles of FOLFOX 6

Principal Investigator: Peter Kozuch, M.D.



A Phase II open- labeled, prospective study to determine the efficacy of pre-operative
chemotherapy with six cycles of modified FOLFOX 6 followed by total mesorectal excision
(TME) followed by an additional six cycles of FOLFOX 6.

The objectives of this study are the following:

1. The primary endpoint of this trial is pathologic complete response (response rate).

2. Secondary endpoints will include observation of overall pathologic response rate,
correlation of pathologic staging with pre-operative ultrasound and pelvic MRI staging,
as well as observation of toxic side effects, patterns of disease relapse, disease-free
survival outcomes and overall survival outcomes.

Background Locally advanced rectal carcinoma continues to be a major oncologic problem in
the United States. Several landmark studies have led to the current standard approach to
the care of patients with stage II and III rectal cancer. In 1990 adjuvant 5- fluorouracil
based chemoradiation became the accepted standard of care on the basis of two randomized
trials. During the following two decades significant modifications were made to both the
administration of chemoradiation therapy and surgery. First, continuous infusion
5-fluorouracil daily concurrent with radiation to was shown to be superior to bolus
5-fluorouracil for 3 consecutive days during weeks 1 and 5 of radiation. The overall rate
of tumor relapse fell from 47% to 37%, and distant metastasis rate fell from 40% to 31%.
Notably, local tumor recurrence was not significantly different between the two chemotherapy
schedules. The improvement in relapse rate translated into a 4 year survival benefit, 70%
versus 60%, favoring the protracted venous infusion of 5-fluorouracil (5-FU).

What is not known, however, is the relative contribution of radiation therapy to survival
outcomes in the setting of chemotherapy programs for rectal cancer. Optimization of
systemic therapy appears to have the most significant impact on survival outcomes. Firstly,
patients may begin full systemic therapy with the regimen that has currently been identified
as the most effective adjuvant treatment of stage III colon cancer. This relatively prompt
initiation of 'full systemic dose' chemotherapy is in stark contrast to the typical paradigm
of a 3-4 week interval between initial consultation and initiation of chemoradiation.
Another theoretical advantage of this proposed trial lies in the fact that full systemic
therapy is relatively uninterrupted. Therefore, the anticipated 6-8 week perioperative
treatment free interval anticipated in this schema compares favorably with the typical 10-12
week perioperative treatment free interval with current standard of care neoadjuvant
chemoradiation. Another important consideration favoring this chemotherapy is substantially
less travel time/treatment time for patients and favorable toxicity profile given the
elimination of daily neoadjuvant radiation.

Treatment Plan

Patients will be given:

- Modified FOLFOX6 will be given neoadjuvantly prior to resection for 3 months (6 cycles)

- Modified FOLFOX6 will be given adjuvantly within 6 weeks following resection for 3
months (6 cycles)

Inclusion Criteria

Inclusion Criteria

1. Patients must consent to participate in the study and must have signed and dated an
IRB-approved consent form conforming to federal and institutional guidelines

2. Patient must have histologically proven adenocarcinoma of the rectum with no distant

3. Tumor stage must be T3N0M0, T1-3 N1M0 assessed by clinical exam, TRUS, MRI and CT.
Pre-operative evidence of T4, N2 or distal lesions (0-6 cm from anal verge) should
receive preoperative RT and not be offered this protocol. Any pT4, pN2 or CRM+
patients should be offered postoperative radiation

4. The proximal border of the tumor must be at or below 12 centimeters of the anal
verge by proctoscopic examination

5. The distal border of the tumor must be at or above 6 cm from the anal verge on
preoperative proctoscopy with the patient in the left lateral decubitus position

6. Patient must have had no prior chemotherapy or pelvic irradiation

7. Karnofsky performance status of 60 or greater; ECOG performance status 0-1

8. Patients should be age 18 years and older

9. Pretreatment absolute neutrophil count >= 1000/mm3 and platelets >= 100,000/mm3

10. Serum creatinine <= 1.5 x ULN; bilirubin <= 1.5 x ULN; ALT<= 2.5 x ULN

Exclusion Criteria

1. Patients can not be receiving any other investigational agents

2. Patients with known metastases will be excluded from the study

3. Patients with history of significant neuropathy or current symptoms of neuropathy

4. Patients with history of allergic reactions attributed to compounds of similar
chemical or biologic composition to oxaliplatin or 5-FU or leucovorin

5. Patients with uncontrolled intercurrent illness not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

6. Pregnant women are excluded from this study because oxaliplatin and 5-FU/LV are
agents with the potential for teratogenic or abortifacient effects. Because there is
an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with oxaliplatin and 5-FU/LV, breastfeeding should be
discontinued if the mother is treated with these agents

7. HIV positive patients

8. Patients with serious comorbid disease which prevents delivery of full treatment
including psychiatric disorders and cardiopulmonary disease

9. No history within the past 5 years of a cancer diagnosis except for non-melanomatous
skin cancers or in situ cervix carcinoma

10. Patients with clinically significant peripheral neuropathy at the time of start of
treatment (defined in the NCI Common Terminology Criteria for Adverse Events Version
3[CTCAE v3.0] as grade 2 or greater neurosensory or neuromotor toxicity

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Pathologic Complete Response

Outcome Time Frame:

3-6 months

Safety Issue:


Principal Investigator

Peter Kozuch, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Beth Israel Medical Center


United States: Institutional Review Board

Study ID:




Start Date:

January 2009

Completion Date:

August 2011

Related Keywords:

  • Rectal Neoplasms
  • Neoplasms
  • Rectal Neoplasms



Beth Israel Medical CenterNew York, New York  10003
St. Luke's Roosevelt Hospital CenterNew York, New York  10019