Radiation Therapy + Fluorouracil for Rectal Cancer

Not currently recruiting at 16 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: 5-fluorouracil, leucovorin, oxaliplatin

Disqualifiers: Metastatic disease, Inflammatory Bowel Disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of combining radiation therapy with chemotherapy for treating rectal cancer before surgery. The combination includes radiation and fluorouracil, a chemotherapy drug that increases cancer cells' sensitivity to treatment, potentially shrinking the tumor so less tissue needs removal during surgery. Eligible participants are those with stage II or stage III rectal cancer that has not spread beyond the rectum. The trial seeks patients with rectal cancer confirmed by specific medical exams and who experience significant cancer-related symptoms. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants an opportunity to contribute to advancements in rectal cancer treatment.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining radiation therapy with fluorouracil is generally well-tolerated by patients with rectal cancer. Studies suggest this treatment effectively manages cancer while keeping side effects, such as skin and digestive issues, relatively mild.

For the FOLFOX treatment, which includes oxaliplatin, leucovorin, and fluorouracil, safety data indicates it is a common choice for advanced colorectal cancer. Most patients tolerate it well, though some may experience side effects like a low white blood cell count, pain, and high blood pressure. Medical care usually manages these side effects.

In summary, both radiation plus fluorouracil and FOLFOX treatments have been widely studied and are considered safe for most patients, with manageable side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for rectal cancer because they combine radiation therapy and chemotherapy in innovative ways that could enhance effectiveness. Unlike the standard of care, which often involves separate or sequential treatments, these approaches integrate radiation therapy with continuous infusion of fluorouracil and varying courses of FOLFOX-6 chemotherapy. This combination aims to improve tumor shrinkage before surgery, potentially increasing surgical success rates and reducing cancer recurrence. Additionally, the use of oxaliplatin and leucovorin calcium alongside fluorouracil in some trial arms offers a more comprehensive attack on cancer cells, which might lead to better patient outcomes compared to traditional treatment methods.

What evidence suggests that this trial's treatments could be effective for rectal cancer?

Research has shown that combining radiation therapy with the drug fluorouracil can effectively shrink tumors in rectal cancer. This approach reduces tumor size before surgery, facilitating easier removal. In this trial, participants in different groups will receive varying treatment combinations. One group will undergo chemoradiation therapy with fluorouracil, followed by surgery. Other groups will receive additional FOLFOX chemotherapy (a mix of fluorouracil, oxaliplatin, and leucovorin) after chemoradiation and before surgery. Specifically, one study found that the five-year disease-free survival rate for patients receiving FOLFOX was about 80.8%, indicating a strong chance of controlling the cancer and preventing its return. Combining these treatments aims to kill cancer cells more effectively and improve overall patient outcomes. ^{3 6 7 8 9}

Who Is on the Research Team?

Julio Garcia-Aguilar, MD, PhD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with stage II or III rectal cancer, who can perform daily activities on their own or need some help (ECOG 0-1). They must have a tumor within 12 cm of the anal verge and no history of certain diseases like inflammatory bowel disease, familial adenomatous polyposis, or recent heart issues. Prior pelvic radiation treatments disqualify them. Adequate organ function and agreement to use birth control are required.

Inclusion Criteria

My rectal cancer is confirmed and is within 12 cm from the anal opening.

I can be part of the study if MRI can stage my condition due to a high-grade obstruction.

I have hereditary non-polyposis colorectal cancer and meet other study requirements.

Exclusion Criteria

I am allergic to 5-fluorouracil, leucovorin, or oxaliplatin.

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.0 times institutional upper limit of normal (ULN)

Serum creatinine =< 1.5 times ULN

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemoradiation

Participants undergo radiation therapy once daily 5 days a week for 5 weeks and receive fluorouracil intravenously continuously over 24 hours 7 days a week for 6 weeks

6 weeks

Chemotherapy

Beginning 4 weeks after completion of chemoradiation therapy, participants receive modified FOLFOX-6 chemotherapy. Treatment repeats every 14 days for 2 to 6 courses depending on the group

4-12 weeks

Surgery

Participants undergo standard surgical resection after completion of chemoradiation and chemotherapy

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Conventional Surgery
• Fluorouracil
• Leucovorin Calcium
• Oxaliplatin
• Radiation Therapy

Trial Overview The study tests how well radiation therapy combined with fluorouracil chemotherapy works compared to adding more drugs (oxaliplatin and leucovorin) before surgery. The goal is to shrink tumors and spare healthy tissue. It includes DNA analysis and other lab tests to see how patients respond.

How Is the Trial Designed?

Group I: Group 4 (chemotherapy, FOLFOX, conventional surgery) Experimental Treatment 9 Interventions

All patients undergo chemoradiation therapy comprising radiation therapy once daily 5 days a week for 5 weeks and fluorouracil IV continuously over 24 hours 7 days a week for 6 weeks. Beginning 4 weeks after completion of chemoradiation therapy, patients receive modified FOLFOX-6 chemotherapy as in group II. Treatment repeats every 14 days for 6 courses. After the last week of post- radiation chemotherapy, patients undergo standard surgical resection. Patients then receive 3 additional courses of FOLFOX-6 chemotherapy or other chemotherapy off study as directed by the physician.

Group II: Group 3 (chemotherapy, FOLFOX, conventional surgery) Experimental Treatment 9 Interventions

All patients undergo chemoradiation therapy comprising radiation therapy once daily 5 days a week for 5 weeks and fluorouracil IV continuously over 24 hours 7 days a week for 6 weeks. Beginning 4 weeks after completion of chemoradiation therapy, patients receive modified FOLFOX-6 chemotherapy as in group II. Treatment repeats every 14 days for 4 courses. After the last week of post-radiation chemotherapy, patients undergo standard surgical resection.

Group III: Group 2 (Closed to Enrollment) Experimental Treatment 9 Interventions

All patients undergo chemoradiation therapy comprising radiation therapy once daily 5 days a week for 5 weeks and fluorouracil IV continuously over 24 hours 7 days a week for 6 weeks. Beginning 4 weeks after completion of chemoradiation therapy, patients receive modified FOLFOX-6 chemotherapy comprising oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours on days 1-2. Treatment repeats every 14 days for 2 courses. After the last week of post-radiation chemotherapy, patients undergo standard surgical resection.

Group IV: Group 1 (Closed to Enrollment) Experimental Treatment 7 Interventions

All patients undergo chemoradiation therapy comprising radiation therapy once daily 5 days a week for 5 weeks and fluorouracil intravenously continuously over 24 hours 7 days a week for 6 weeks. Patients undergo standard surgical resection after completion of chemoradiation therapy..

Fluorouracil is already approved in United States, European Union, Canada for the following indications:

Approved in United States as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Skin cancer

Approved in European Union as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Approved in Canada as 5-Fluorouracil for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The Phase I study determined that the maximal tolerated dose of capecitabine combined with standard radiotherapy for rectal cancer is 1600 mg/m²/day, which is important for future treatment protocols.

Dose-limiting toxicities were observed at lower doses, including Grade 3 diarrhea and skin toxicity, indicating that while capecitabine can be effective, careful monitoring for side effects is necessary during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter dose-finding study of concurrent capecitabine and radiotherapy as adjuvant treatment for operable rectal cancer. Souglakos, J., Androulakis, N., Mavroudis, D., et al.[2019]

In a phase 2 trial involving 63 anal cancer patients, dose-painted intensity modulated radiation therapy (DP-IMRT) did not significantly reduce the overall rate of grade 2+ gastrointestinal and genitourinary adverse events compared to conventional treatment, but it did show a notable reduction in grade 3+ gastrointestinal (21% vs. 36%) and dermatologic (23% vs. 49%) toxicities.

DP-IMRT was found to be feasible, but a high rate of pretreatment planning revisions (81%) highlights the need for careful real-time quality assurance in radiation therapy to ensure patient safety and treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Kachnic, LA., Winter, K., Myerson, RJ., et al.[2022]

Neoadjuvant chemoradiation, particularly with fluorouracil (5-FU) plus radiation, is now the preferred treatment for stage II/III rectal cancer, showing lower local relapse rates and better safety compared to postoperative treatments.

Capecitabine (Xeloda) plus radiation has been found to be as effective as 5-FU plus radiation, making it a viable alternative, while combinations with oxaliplatin or irinotecan show promise for improved outcomes and warrant further investigation in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemoradiation for rectal cancer: is more better? Patel, A., Puthillath, A., Yang, G., et al.[2018]

A series of clinical trials initiated by the Gastrointestinal Tumor Study Group in the 1970s explored the effectiveness of radiation therapy combined with chemotherapy for treating pancreatic, rectal, and gastric adenocarcinomas, which were previously thought to be resistant to radiation.

The trials included various treatment protocols, such as comparing high-dose radiation with chemotherapy to lower doses, and consistently used 5-fluorouracil as a chemotherapeutic agent, indicating a systematic approach to improving outcomes for patients with locally unresectable tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An organized multi-institutional interdisciplinary evaluation of role of radiation therapy alone or combined with chemotherapy in treatment of adenocarcinoma of the gastrointestinal tract. Douglass, HO., Stablein, DM., Thomas, PR.[2007]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39671537/

Updated Results of the FOWARC Study After a Median ... Patients achieving pathologic complete response had 10-year DFS, LR, and OS rates of 84.3%, 3.0%, and 92.4%, respectively. No significant ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5470972/

Meta-analysis of oxaliplatin-based versus fluorouracil-based ... A meta-analysis was conducted to compare oxaliplatin-based with fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy for locally advanced ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO-24-01676

Neoadjuvant Modified Infusional Fluorouracil, Leucovorin, ... Pelvic radiotherapy mainly reduces pelvic local recurrence, but neoadjuvant mFOLFOX6 alone maintained a low LR rate of about 10% in this study.

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2303269

Preoperative Treatment of Locally Advanced Rectal Cancer Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy ...

5. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70377-8/abstract

Oxaliplatin, fluorouracil, and leucovorin versus ... Adjuvant FOLFOX improves disease-free survival compared with fluorouracil plus leucovorin in patients with locally advanced rectal cancer after preoperative ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/25201358/

Oxaliplatin, fluorouracil, and leucovorin versus ... 3-year disease-free survival was 71·6% (95% CI 64·6-78·6) in the FOLFOX group and 62·9% (55·4-70·4) in the fluorouracil plus leucovorin group (hazard ratio 0· ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4127629/

Safety Analysis of FOLFOX4 Treatment in Colorectal ... FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin) is a standard regimen for the treatment of advanced colorectal cancer. Its dose intensity and safety ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.21.02628

Final Analysis of 3 Versus 6 Months of Adjuvant Oxaliplatin ... 11; Data Supplement). For patients with high-risk disease, outcomes were similar for 3 and 6 months of treatment with mFOLFOX6 (HR, 1.01; 95% CI ...

9. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2837317

Older Age Threshold for Oxaliplatin Benefit in Stage II to III ... The analysis results showed that oxaliplatin treatment was not associated with improved survival among patients with stage III disease aged ...