Pelvic Radiotherapy With Concurrent Neoadjuvant FOLFOX for Patients With Newly Diagnosed Rectal Adenocarcinoma (GCC 1314)

Phase II Trial of Low Dose Whole Pelvic Radiotherapy With Concurrent Neoadjuvant FOLFOX for Patients With Newly Diagnosed T3N0M0, T2N1M0, or T3N1M0 Rectal Adenocarcinoma

The purpose of this study is to assess the effects, both good and bad, of adding very low dose fractionated radiation therapy (LDFRT) to the pelvis, with FOLFOX chemotherapy prior to surgery. Standard pelvic radiation therapy given once a day (Monday through Friday) over approximately 5.5 weeks is not given in this study. You will receive 6 cycles of FOLFOX (each cycle is 2 weeks) and you will also get an LDFRT to your pelvis given twice a day on the first two days of each cycle.

Study Overview

• Status: Terminated
• Conditions: Rectal Adenocarcinoma
• Intervention / Treatment: Drug: FOLFOX {5-fluorouracil (5-FU), leucovorin, and oxaliplatin}; Radiation: Low dose fractionated radiation therapy (LDFRT)

Detailed Description

The current standard of care for treatment of locally advanced rectal cancer consists of neoadjuvant whole pelvic RT with radiosensitizing single-agent 5-FU followed by surgery and adjuvant full dose chemotherapy (typically FOLFOX). For all clinical T3, T4, and/or lymph node positive rectal cancer patients the standard neoadjuvant radiation dose per fraction is 180 cGy delivered on consecutive weekdays over 5.5 weeks for a total of 5040 cGy. A potentially paradigm-changing approach is currently being investigated in a phase II/III trial in which neoadjuvant RT is omitting in favor of using full dose FOLFOX chemotherapy based on provocative data published from Memorial Sloan Kettering Cancer Center. We hypothesize that whole pelvic LDFRT using 40 cGy fractions for a total of 960 cGy can be safely added concurrently to neoadjuvant full dose FOLFOX as an alternative to standard neoadjuvant 5-FU chemoradiation. We further hypothesize that using LDFRT as a chemopotentiatior will significantly increase the pCR rate as reported by the Memorial Sloan Kettering pilot study of 27%. Lastly, due to the significantly lower radiation dose per fraction and lower total radiation dose we expect that this novel strategy will not cause higher rates of severe toxicity compared to neoadjuvant FOLFOX alone.

Specifically, this phase II trial intends to determine whether 6 cycles of neoadjuvant FOLFOX with concurrent LDFRT followed by comprehensive restaging and TME achieves favorable outcomes for patients with T3N0M0, T3N1M0, or T2N1M0 rectal cancer. As mentioned above, the current standard of care for all locally advanced rectal cancer patients includes radiosensitizing 5-FU and concurrent whole pelvic RT to 5040 Gy in 180 Gy once daily fractions. Per the proposed protocol, T3N0M0, T3N1M0, or T2N1M0 rectal cancer patients who are eligible to undergo a low anterior resection would receive whole pelvic RT to 960 cGy in 40 cGy fractions delivered twice daily on days 1-2 of each cycle of FOLFOX chemotherapy for a total of 6 cycles.

Eligible study subjects include adults who are candidates for curative intent sphincter-sparing surgery and who lack high-risk features, particularly tumor encroaching upon the mesorectal fascia (within 3 mm) as determined by pre-treatment endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI) or distal rectal tumors (<5 cm from the anal verge).

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Ummc Msgcc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. ≥ 18 years old at diagnosis.
2. ECOG Performance Status 0, 1, or 2.
3. Biopsy-proven diagnosis of rectal adenocarcinoma.
4. Radiographically measurable or clinically evaluable disease by CT scan of chest/abdomen/pelvis with and without contrast ≤ 28 days prior to registration.
5. Clinical AJCC 7th edition stage T2N1M0, T3N0M0 or T3N1M0 based on physical examination, CT scan chest/abdomen/pelvis, and pelvic MRI or endorectal ultrasound.
6. Preoperative proctoscopy confirming tumor extent as no less than 5 cm and no greater than 12 cm from the anal verge.
7. Evaluation by a surgical oncologist, radiation oncologist, and medical oncologist ≤ 28 days prior to registration.
8. Confirmation by a surgeon that the patient is able to undergo a low anterior resection with total mesorectal excision ≤ 28 days prior to registration.
9. In the absence of a being treated on a clinical trial, the patient would be recommended to receive neoadjuvant chemoradiation followed by curative intent surgery.

10. The following laboratory values obtained ≤ 28 days prior to registration:

    • Absolute neutrophil count (ANC) ≥ 1500/mm3.
    • Platelet count ≥ 100,000/mm3.
    • Hemoglobin > 8.0 g/dL. May transfuse to meet eligibility.
    • Total bilirubin ≤ 1.5 x upper limit of normal (ULN).
    • SGOT (AST) ≤ 3 x ULN.
    • SGPT (ALT) ≤ 3 x ULN.
    • Creatinine ≤ 1.5 x ULN.
11. Negative pregnancy test (B-HCG) within 7 days prior to registration for women of childbearing potential.
12. Did the patient provide study-specific informed consent prior to study entry?
13. Willingness to return to the enrolling medical site for all study assessments.

Exclusion Criteria:

1. Clinical T4 tumor.
2. Primary surgeon indicates the need for an abdominal perineal resection (APR) at baseline.
3. Previous pelvic RT.
4. Autoimmune disease such as scleroderma, lupus, or inflammatory bowel disease.
5. Tumor < 3 mm from the mesorectal fascia as seen on MRI or endorectal ultrasound.
6. Tumor-induced symptomatic bowel obstruction.
7. Chemotherapy (including hormonal therapy) within the past 5 years from date of registration.
8. Other invasive malignancies within past 5 years from date of registration.
9. Pregnant or nursing women.
10. Men or women of childbearing potential who are unwilling to employ adequate contraception.
11. Other co-morbid conditions that, based on the judgment of the physicians obtaining informed consent, would make the patient inappropriate for this study.
12. Any conditions that would preclude a patient from completing all study assessments.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Pelvic Radiotherapy With Concurrent Neoadjuvant FOLFOX; Part I: FOLFOX: combination of drugs administered in a specific sequence as prescribed below.; Oxaliplatin: 85 mg/m2 intravenously (IV) over 2 hours; Leucovorin: 200 mg/m2 IV bolus over 2 hours; 5-FU: 400 mg/m2 IV bolus over 5-15 minutes, then 2,400 mg/m2 continuous IV infusion over 46-48 hours Part II: Low dose fractionated radiation therapy (LDFRT) Intensity-modulated, bone marrow sparing, whole pelvic radiation therapy 40 cGy fractions twice per day delivered at least 4-6 hours apart on the first 2 days of each chemotherapy cycle for a total of 6 cycles

Drug: FOLFOX {5-fluorouracil (5-FU), leucovorin, and oxaliplatin}; see arm description; Radiation: Low dose fractionated radiation therapy (LDFRT); see arm description

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Outcome Measure (Overall Survival Rate)	Overall survival rate of patients who receive a neoadjuvant full dose FOLFOX plus the addition of concurrent LDFRT result in a pCR response rate of at least 35%.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary Outcome Measure (Number of Adverse Events)	Number of adverse events caused from the administration of neoadjuvant concurrent LDFRT-FOLFOX while maintaining a high rate of pelvic R0 resection compared to standard preoperative chemoradiation and total mesorectal excision surgery.	1 year

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Investigators: Principal Investigator: Shahed Badiyan, MD, Ummc Msgcc

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Actual): October 5, 2018
• Study Completion (Actual): October 5, 2018

Study Registration Dates

• First Submitted: December 10, 2014
• First Submitted That Met QC Criteria: December 17, 2014
• First Posted (Estimate): December 18, 2014

Study Record Updates

• Last Update Posted (Actual): November 4, 2021
• Last Update Submitted That Met QC Criteria: October 6, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Pelvic Radiotherapy; Rectal Adenocarcinoma
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Adenocarcinoma; Rectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Leucovorin
• Other Study ID Numbers: HP-00060641