Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients with Locally Advanced Rectal Cancer Undergoing Surgery

Protocol: NCCTG-N1048

Full Title

A Phase II/III trial of Neoadjuvant FOLFOX, with Selective Use of Combined Modality Chemoradiation versus Preoperative Combined Modality Chemoradiation for Locally Advanced Rectal Cancer Patients Undergoing Low Anterior Resection with Total Mesorectal Excision.


This randomized phase II/III trial studies how well chemotherapy alone compared to chemotherapy plus radiation therapy works in treating patients with rectal cancer that has spread from where it started to nearby tissue or lymph nodes undergoing surgery. Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, fluorouracil, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells. It is not yet known whether chemotherapy alone is more effective then chemotherapy plus radiation therapy in treating rectal cancer.

Study Objective


I. To assure that neoadjuvant leucovorin calcium, fluorouracil, and oxaliplatin (FOLFOX) followed by selective use of 5-fluorouracil, capecitabine, and radiation therapy (5FUCMT) group (Group 1) maintains the current high rate of pelvic R0 resection and is consistent with non-inferiority for time to local recurrence (TLR). (Phase II)

II. To compare neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) to standard 5FUCMT (Group 2) with respect to the co-primary endpoints of the time to local recurrence (TLR) and disease-free survival (DFS). (Phase III)


I. To determine if the neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) is non-inferior to the standard group 5FUCMT (Group 2) with respect to the proportion of patients who achieve a pathologic complete response (pCR) at the time of surgical resection.

II. To determine if the neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) is non-inferior to the standard 5FUCMT (Group 2) with respect to overall survival.

III. To evaluate and compare the adverse event profile and surgery complications between two groups.

IV. To estimate the proportion of patients in the selective group (Group 1) who receive: 1) pre-operative 5FUCMT; 2) post-operative 5FUCMT; 3) either pre- or post-operative 5FUCMT.


I. To compare bowel function in patients randomized to the neoadjuvant FOLFOX followed by selective use of 5FUCMT vs. standard 5FUCMT at approximately 1 and 2 years post-operatively.

II. To compare sexual function separately within men and within women between groups at approximately 1 and 2 years post-operatively.

III. To compare bladder function between groups at approximately 1 and 2 years post-operatively.

IV. To compare health-related quality of life between groups at 1 and 2 years postoperatively.

V. To assess the correlation between bladder, bowel, and sexual function and quality of life; to investigate factors associated with bladder, bowel, and sexual dysfunction; to compare bladder and bowel function over time between genders; and to perform subgroup analyses based on other sociodemographic factors.

VI. To evaluate the feasibility of implementing the Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) in a National Cancer Institute (NCI)-sponsored treatment trial.

VII. To evaluate the feasibility of implementing the PRO-CTCAE at Alliance sites.

VIII. To evaluate the feasibility of patients self-reporting symptoms during treatment by using the PRO-CTCAE.

IX. To evaluate and compare patients’ self-reported symptom burden during treatment between groups using the PRO-CTCAE system.

X. To evaluate whether exposure to patient-reported symptoms influences CTCAE.

XI. To prospectively use molecular inversion probe (MIP) array technology and mass spectrometry-based genotyping to identify copy number aberrations and somatic mutations that mediate tumor formation using formalin-fixed, paraffin-embedded (FFPE) tumor tissue from patients participating in the current study.

XII. To correlate the MIP array copy number and mutational data from patients with locally advanced rectal cancer with clinical outcome in each treatment cohort. The clinical outcomes include pathologic complete response, time to recurrence, time to pelvic recurrence, and overall survival.

XIII. To identify immune markers for response to neoadjuvant chemotherapy or chemoradiation using very well established, validated immunologic assays.

XIV. To investigate the ability of neoadjuvant FOLFOX or chemoradiation to augment anti-tumor immunity against rectal cancer.

XV. To identify novel immune targets in rectal cancer.

XVI. To determine whether germline genetic variants in candidate genes of interest are associated with response and/or toxicity to platinum and 5FU-based chemotherapy.

XVII. To determine whether germline genetic variants in candidate genes of interest are associated with response and/or toxicity to radiation therapy.

XVIII. To assess whether genetic risk variants identified in genome-wide association studies of colorectal cancer susceptibility are associated with rectal cancer clinical outcome and response to therapy.

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

GROUP I (FOLFOX): Patients receive neoadjuvant chemotherapy comprising oxaliplatin intravenously (IV) over 2 hours and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously on days 1-2. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients with at least 20% of tumor regression undergo low-anterior resection (LAR) with total mesorectal excision (TME). Patients with less than 20% of tumor regression undergo chemoradiation as in group 1 before proceeding to LAR with TME.

GROUP II (5FUCMT): Patients receive fluorouracil IV continuously 5 or 7 days a week for 5.5 weeks or capecitabine orally (PO) twice daily (BID) 5 days a week for 5.5 weeks. Patients also undergo 3-dimensional conformal (3D-CRT) or intensity-modulated radiation therapy (IMRT) 5 days a week for approximately 5.5 weeks. Patients then undergo LAR with TME.

Patients in both groups may receive adjuvant chemotherapy comprising FOLFOX and/or 5FUCMT.

After completion of study treatment, patients are followed up for up to 8 years.

Are you eligible?

Inclusion Criteria:

Diagnosis of rectal adenocarcinoma

Radiologically measurable or clinically evaluable disease

Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0, 1 or 2

For this patient, the standard treatment recommendation in the absence of a clinical trial would be combined modality, neoadjuvant chemoradiation followed by curative intent surgical resection

Candidate for sphincter-sparing surgical resection prior to initiation of neoadjuvant therapy according to the primary surgeon

Clinical stage: T2N1, T3N0, T3N1

N2 disease is to be estimated as four or more lymph nodes that are >= 10 mm

Clinical staging should be estimated based on the combination of the following assessments: physical exam by the primary surgeon, computed tomography (CT) or positron emission tomography (PET)/CT scan of the chest/abdomen/pelvis and either a pelvic magnetic resonance imaging (MRI) or an ultrasound (endorectal ultrasound [ERUS]); if a pelvic MRI is performed, it is acceptable to perform CT of the chest/abdomen, omitting CT imaging of the pelvis

Absolute neutrophil count (ANC) >= 1,500/mm^3

Platelet count >= 100,000/mm^3

Hemoglobin > 8.0 g/dL

Total bilirubin =< 1.5 x upper limit of normal (ULN)

Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 x ULN

Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN

Creatinine =< 1.5 times ULN

Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only

Patient of child-bearing potential is willing to employ adequate contraception

Provide informed written consent

Willing to return to enrolling medical site for all study assessments

Exclusion Criteria:

Clinical T4 tumors

Primary surgeon indicates need for abdominoperineal (APR) at baseline

Evidence that tumor is adherent to or invading the mesorectal fascia on imaging studies such that the surgeon would not be able to perform an R0 resection (one with negative margins)

Tumor is causing symptomatic bowel obstruction (patients who have had a temporary diverting ostomy are eligible)

Chemotherapy within 5 years prior to registration; (hormonal therapy is allowable if the disease free interval is >= 5 years)

Any prior pelvic radiation

Other invasive malignancy =< 5 years prior to registration; exceptions are colonic polyps, non-melanoma skin cancer or carcinoma-in-situ of the cervix

Any of the following

Pregnant women

Nursing women

Men or women of childbearing potential who are unwilling to employ adequate contraception

Co-morbid illnesses or other concurrent disease which, in the judgment of the clinician obtaining informed consent, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

Colon Cancer Rectal Cancer Gastrointestinal Cancers