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Phase I Study of Preoperative Radiation Therapy With Concurrent Protracted Continuous Infusion 5-FU and Dose Escalating Oxaliplatin Followed by Surgery, 5-FU, and Leucovorin for Locally Advanced (T3 and T4) Rectal Adenocarcinoma

Phase 1
18 Years
Not Enrolling
Adenocarcinoma of the Rectum, Mucinous Adenocarcinoma of the Rectum, Signet Ring Adenocarcinoma of the Rectum, Stage IIA Rectal Cancer, Stage IIB Rectal Cancer, Stage IIC Rectal Cancer, Stage IIIA Rectal Cancer, Stage IIIB Rectal Cancer, Stage IIIC Rectal Cancer

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Trial Information

Phase I Study of Preoperative Radiation Therapy With Concurrent Protracted Continuous Infusion 5-FU and Dose Escalating Oxaliplatin Followed by Surgery, 5-FU, and Leucovorin for Locally Advanced (T3 and T4) Rectal Adenocarcinoma


I. To identify maximally tolerated dose (MTD) and dose limiting toxicity (DLT) of
oxaliplatin when combined preoperatively with concurrent radiation therapy (XRT) and
fluorouracil (5-FU) by PVI.

II. To evaluate the resection rate for T4 rectal cancers, the pathologic CR rate for T3 and
T4 rectal cancers, and the expected versus actual type of resection (APR vs. LAR vs.
LAR/coloanal anastomosis).

III. To make preliminary observations of patient survival and patterns of recurrence for
this treatment combination.

IV. To evaluate anastomotic and sphincter function following pre-op combined modality

OUTLINE: This is a dose-escalation study of preoperative oxaliplatin.

Patients receive fluorouracil IV continuously with concurrent radiotherapy for 5.5 weeks.
Patients also receive oxaliplatin IV over 2 hours on day 1 of weeks 1, 3, and 5.

Cohorts of 5 patients each receive escalating doses of oxaliplatin until the maximum
tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which
at least 2 of 5 patients experience dose-limiting toxicity. Additional patients are treated
at the MTD.

Patients undergo surgery 6-8 weeks after completing preoperative chemotherapy and
radiotherapy. The surgical procedure is determined by the extent of the tumor before
preoperative therapy. The type of operative procedure may be abdominoperineal resection, low
anterior resection (LAR), or LAR/coloanal anastomosis.

Postoperative chemotherapy begins within 6 weeks after surgery, comprising leucovorin
calcium and fluorouracil IV on days 1-5. Treatment repeats every 21 days for 4 courses.

Patients are followed every 3 months for 2.5 years, every 6 months for 3 years, then
annually for 5 years.

Inclusion Criteria:

- Histologically confirmed, locally advanced, non-metastatic primary T3 or T4 primary
adenocarcinoma of the rectum

- No evidence of tumor outside of the pelvis including liver metastases, peritoneal
seeding, or metastatic inguinal lymphadenopathy

- No intra-operative radiotherapy (IORT) or brachytherapy will be allowed

- The distal border of the tumor must be at or below the peritoneal reflection, defined
as within 12 centimeters of anal verge by proctoscopic examination

- Transmural penetration of tumor through the muscularis propria must be demonstrated
by either of the following:

- CT scan plus endorectal ultrasound or


- Tumors must be defined prospectively by the surgeon as clinically resectable or not;
clinically resectable tumors will be defined by the surgeon as mobile and completely
resectable with negative margins based on the routine examination of the
non-anesthetized patient; before pre-op treatment, the surgeon should estimate and
record the type of resection anticipated: APR, LAR, or LAR/coloanal anastomosis

- The tumor may be clinically fixed or initially not completely resectable, clinical
stage T4, N0-2, M0 based on the presence of at least one of the following criteria:

- Clinically fixed tumors on rectal examination with tumor adherent to the pelvic
sidewall or sacrum

- Sciatica attributed to sacral root invasion with CT scan/MRI evidence of the
lack of clear tissue plane will be considered evidence of fixation

- Hydronephrosis on CT scan or IVP or ureteric or bladder invasion as documented
by cystoscopy and cytology or biopsy, or invasion into prostate

- Vaginal or uterine involvement

- ECOG performance status 0-2 and surgical evaluation confirms the patient's medical
condition would tolerate the proposed surgical procedure

- Caloric intake should be >= 1500 kilocalories/d

- WBC >= 3500/uL

- Platelets >= 100,000/uL

- Serum creatinine =< 2.0 mg/dL

- Serum bilirubin less than 2.0 mg/dL

- Alk Phos =< 2 x ULN

- SGOT =< 2 x ULN

- CEA should be determined prior to initiation of therapy

- Absence of clinical evidence of high-grade (lumen diameter < 1cm) large bowel
obstruction, unless diverting colostomy has been performed

- Pregnant or lactating women are not eligible

- Women of childbearing potential and sexually active males are strongly advised to use
an accepted and effective method of contraception

- No prior chemotherapy or pelvic irradiation therapy

- No previous or concurrent malignancy is allowed, except:

- Nonmelanoma skin cancer or in situ cervical cancer

- Treated non-pelvic cancer from which the patient has been continuously disease
free more than five years

- No active inflammatory bowel disease or other serious medical illness which might
limit the ability of the patient to receive protocol therapy

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of oxaliplatin when combined with radiation therapy and fluorouracil based on the incidence of DLT as assessed by CTC version 2.0

Outcome Time Frame:

5 weeks

Safety Issue:


Principal Investigator

Daniel Haller

Investigator Role:

Principal Investigator

Investigator Affiliation:

Eastern Cooperative Oncology Group


United States: Food and Drug Administration

Study ID:




Start Date:

May 1999

Completion Date:

Related Keywords:

  • Adenocarcinoma of the Rectum
  • Mucinous Adenocarcinoma of the Rectum
  • Signet Ring Adenocarcinoma of the Rectum
  • Stage IIA Rectal Cancer
  • Stage IIB Rectal Cancer
  • Stage IIC Rectal Cancer
  • Stage IIIA Rectal Cancer
  • Stage IIIB Rectal Cancer
  • Stage IIIC Rectal Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Rectal Neoplasms
  • Cystadenocarcinoma



Eastern Cooperative Oncology Group Boston, Massachusetts  02215