Chemoradiation for Rectal Cancer

(SMART TNT Trial)

Overseen By Zuzel Rodriguez

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Miami

Must not be taking: Anti-anxiety agents

Disqualifiers: Metastatic disease, Synchronous cancer, others

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

Compensation: Varies

Number of Visits: Unknown

25 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this research study is to find out how safe and effective is treating patients with locally advanced rectal cancer (LARC) with chemotherapy first and then follow with radiation therapy to a higher dose than what is usually delivered and see if patients could have complete response and be spared from surgery.

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.

What data supports the effectiveness of the treatment for rectal cancer?

Research shows that using 5-fluorouracil (5-FU) with radiation therapy before surgery can reduce the chance of cancer coming back and improve survival rates for rectal cancer patients. Capecitabine, an oral form of 5-FU, has similar effectiveness when combined with radiation. Adding oxaliplatin to these treatments has shown promising results in improving responses in early trials. ^{1 2 3 4 5}

Is chemoradiation for rectal cancer generally safe for humans?

Chemoradiation for rectal cancer, using drugs like 5-fluorouracil (5-FU) and capecitabine (Xeloda), is generally considered safe, but it can cause side effects like diarrhea and mouth sores. These side effects can be severe in some cases, so it's important to monitor and manage them during treatment. ^{1 3 6 7 8}

What makes the chemoradiation treatment for rectal cancer unique?

This treatment combines 5-fluorouracil (5-FU), capecitabine, leucovorin, and oxaliplatin, which together enhance the effectiveness of radiation therapy by improving tumor response and potentially reducing recurrence. Capecitabine, an oral drug, offers a convenient alternative to intravenous 5-FU, and the addition of oxaliplatin may lead to better outcomes, although further studies are needed to confirm its routine use. ^{1 3 4 9 10}

Research Team

Benjamin Spieler, MD

Principal Investigator

University of Miami

Eligibility Criteria

This trial is for adults with newly diagnosed rectal cancer that hasn't spread beyond the pelvis. Participants must have a certain level of physical fitness (ECOG 0-2), acceptable liver function, and no severe heart conditions or immune deficiencies. Pregnant women and those with metal implants incompatible with MRI are excluded.

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document

My tumor is within 18 cm of the anal verge.

Serum liver function tests values within the range of 1.5 x Upper Limit of Normal (within 6 weeks of enrollment)

Exclusion Criteria

Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity

I have had radiation therapy in the pelvic area before.

I do not have severe infections needing IV antibiotics or active TB.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Chemotherapy

Participants receive neoadjuvant chemotherapy with either FOLFOX, mFOLFIRINOX, or CAPOX

12-16 weeks

Chemo-radiation Therapy (Plan I)

Participants receive MRI-guided pelvic IMRT and concurrent chemotherapy

5 weeks

Radiation Therapy Boost (Plan II)

Participants not achieving complete Clinical Response receive an accelerated radiation therapy boost

1 week

Follow-up

Participants are monitored for safety, effectiveness, and long-term outcomes after treatment

Up to 30 months

Treatment Details

Interventions

• 5-fluorouracil
• Accelerated Radiation Therapy
• Capecitabine
• Intensity-modulated radiation therapy
• Leucovorin
• Oxaliplatin

Trial Overview The study tests if starting with chemotherapy followed by higher-than-usual doses of radiation can help patients avoid surgery while effectively treating locally advanced rectal cancer. The chemo drugs used include 5-fluorouracil, Leucovorin, Oxaliplatin, and Capecitabine.

Participant Groups

Group I: SMART TNT Plan II Experimental Treatment 1 Intervention

Plan II boost RT (1 week): For participants not achieving cCR after chemo-radiation. Participants will receive MRI-guided accelerated radiation therapy (ART) boost to the primary tumor. Participants achieving a cCR will continue to follow-up. Participants still showing residual tumor will undergo standard of care treatment including surgery and adjuvant chemotherapy per institutional guidelines during follow-up.

Group II: SMART TNT Plan I Experimental Treatment 6 Interventions

Participants will initiate therapy with neoadjuvant chemotherapy of either six (6) 14-day cycles of 5-fluorouracil + leucovorin + oxaliplatin (FOLFOX), six (6) 14-day cycles of 5-fluorouracil + leucovorin + irinotecan + oxaliplatin (mFOLFIRINOX), or four (4) 21-day cycles of capecitabine+oxaliplatin (CAPOX). Participants will then receive chemo-radiation therapy according to Plan I as follows: Plan I (5 weeks): * MRI-guided pelvic IMRT to the Planning Tumor Volume (PTV) at a dose of 50 Grays (gy) delivered in 25 fractions (fx) over 5 weeks. * Concurrent chemotherapy beginning on Day 1 of RT either: * 5-FU delivered 5 or 7 days per week. * Capecitabine (Xeloda) delivered 5 days per week. After completing Plan I, participants achieving complete Clinical Response (cCR) after completing Plan I chemo-radiation will forgo the Plan II boost and continue to follow-up. Participants not achieving cCR will begin Plan II, one week after completing Plan I.

5-fluorouracil is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Esophageal cancer
• Anal cancer

Approved in European Union as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Esophageal cancer
• Anal cancer

Approved in Canada as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Esophageal cancer
• Anal cancer

Approved in Japan as 5-FU for:

• Colorectal cancer
• Breast cancer
• Stomach cancer
• Pancreatic cancer
• Esophageal cancer
• Anal cancer

Who Is Running the Clinical Trial?

University of Miami

Lead Sponsor

Trials

976

Recruited

423,000+

Findings from Research

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]

Adjuvant therapy using 5-fluorouracil/leucovorin (5-FU/LV) regimens and capecitabine has significantly improved 3-year disease-free survival rates in stage III colorectal cancer patients, indicating its efficacy in early disease stages.

The addition of oxaliplatin to 5-FU-based regimens has been confirmed to enhance disease-free survival, establishing it as a standard treatment alongside other chemotherapy options for colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid evolution in colorectal cancer: therapy now and over the next five years. de Gramont, A.[2007]

Oral doxifluridine combined with leucovorin is as effective as intravenous 5-fluorouracil (5-FU) in treating rectal cancer post-surgery, with similar rates of recurrence (6.5% for oral vs. 12.1% for IV).

Patients receiving oral doxifluridine reported a significantly better quality of life compared to those on intravenous 5-FU, with more patients scoring 'good' quality of life at 1 and 2 months after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective randomized trial comparing intravenous 5-fluorouracil and oral doxifluridine as postoperative adjuvant treatment for advanced rectal cancer. Min, JS., Kim, NK., Park, JK., et al.[2022]

In a study involving 67 patients with stage II and III rectal adenocarcinoma, capecitabine was found to be at least as effective as 5-Fluorouracil in adjuvant chemoradiotherapy, with no significant differences in toxicity or overall survival rates.

There was a notable trend towards improved loco-regional recurrence-free survival in patients treated with capecitabine, suggesting it may work better in combination with radiotherapy compared to 5-Fluorouracil.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of protracted infusion 5-fluorouracil and capecitabine in adjuvant chemoradiotherapy for rectal cancer. Kurt, M., Ozkan, L., Kurt, E., et al.[2015]

In a study of 41 patients with lower rectal cancer, four courses of mFOLFOX6 chemotherapy before surgery resulted in a 3-year recurrence-free survival rate of 72.8% and a local recurrence rate of 8.5%, indicating a promising long-term oncological benefit.

Patients with clinical Stage III cancer who received adjuvant chemotherapy after the initial mFOLFOX6 treatment had a significantly higher 3-year recurrence-free survival rate (76.6%) compared to those who did not receive adjuvant therapy (40.0%), suggesting the importance of additional treatment for this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The survival impact of preoperative FOLFOX for resectable locally advanced rectal cancer: the R-NAC-01 study. Ichikawa, N., Homma, S., Funakoshi, T., et al.[2022]

In a study of 86 patients with locally advanced rectal cancer, both neoadjuvant chemotherapy regimens (mFOLFOXIRI and XELOX/SOX) showed similar pathological response rates, with 36.7% for mFOLFOXIRI and 40.5% for XELOX/SOX.

However, mFOLFOXIRI was associated with significantly higher toxicity, as 45% of patients experienced severe neutropenia compared to only 8% in the XELOX/SOX group, indicating that while both regimens are effective, XELOX/SOX may be a safer option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Comparison of mFOLFOXIRI With XELOX/SOX as Neoadjuvant Chemotherapy for Locally Advanced Rectal Cancer. Kodama, H., Terazawa, T., Ishizuka, Y., et al.[2021]

In a study of 50 patients with nonmetastatic colorectal cancer, adverse reactions were more frequent with the XELOX regimen (capecitabine combined with oxaliplatin), particularly neurotoxicity, thrombocytopenia, and neutropenia, compared to capecitabine monotherapy.

The type of capecitabine formulation (innovative vs. generic) did not significantly affect the safety profile; instead, the chemotherapy scheme used was the main factor influencing the occurrence of adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine safety profile, innovative and generic adjuvant formulation of nonmetastatic colorectal cancer. Sánchez-Gundín, J., Torres-Suárez, AI., Fernández-Carballido, AM., et al.[2020]

5-fluorouracil (5-FU) combined with leukovorin is commonly used for treating metastatic colorectal cancer, but it can cause severe gastrointestinal side effects, including stomatitis and diarrhea, which can be life-threatening in up to 30% of patients.

This case report highlights therapy-induced enteritis as a serious complication of 5-FU treatment, emphasizing the need for early recognition and intervention to prevent significant morbidity and mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enteritis as a complication of adjuvant combination chemotherapy using 5-fluorouracil and leukovorin: clinical and helical computed tomographic features. Zamani, R., Heldmann, M.[2022]

In a Phase II trial involving 23 patients with unresectable primary rectal cancer, the combination of oral doxifluridine and leucovorin with pelvic radiation showed promising efficacy, with 23.8% achieving a complete response and 61.9% a partial response.

The treatment was associated with low toxicity levels, primarily Grade 1/2 side effects, with diarrhea being the only Grade 3 toxicity observed in 33.3% of patients, indicating that doxifluridine may be a safer alternative to traditional intravenous chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative chemoradiotherapy with oral doxifluridine plus low-dose oral leucovorin in unresectable primary rectal cancer. Seong, J., Cho, JH., Kim, NK., et al.[2019]

In a study of 11 patients with locally advanced rectal cancer, the combination of oral 5-doxifluridine (5-dFUR) and l-leucovorin with pelvic radiotherapy resulted in two patients achieving pathologically complete remission after treatment, indicating potential effectiveness in improving tumor response.

The treatment was generally well-tolerated, with manageable side effects such as grade 3 diarrhea in one patient and mild nausea and vomiting in three, while no significant hematological toxicity was observed, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Integrated treatment with doxifluridine and radiotherapy in recurrent or primary unresectable rectal cancer. A feasibility study. Di Bartolomeo, M., Bajetta, E., Buzzoni, R., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemoradiation for rectal cancer: is more better? [2018]

2. England pubmed.ncbi.nlm.nih.gov

Rapid evolution in colorectal cancer: therapy now and over the next five years. [2007]

3. United States pubmed.ncbi.nlm.nih.gov

A prospective randomized trial comparing intravenous 5-fluorouracil and oral doxifluridine as postoperative adjuvant treatment for advanced rectal cancer. [2022]

4. Greece pubmed.ncbi.nlm.nih.gov

Comparison of protracted infusion 5-fluorouracil and capecitabine in adjuvant chemoradiotherapy for rectal cancer. [2015]

5. Japan pubmed.ncbi.nlm.nih.gov

The survival impact of preoperative FOLFOX for resectable locally advanced rectal cancer: the R-NAC-01 study. [2022]

6. Greece pubmed.ncbi.nlm.nih.gov

Retrospective Comparison of mFOLFOXIRI With XELOX/SOX as Neoadjuvant Chemotherapy for Locally Advanced Rectal Cancer. [2021]

7. Spain pubmed.ncbi.nlm.nih.gov

Capecitabine safety profile, innovative and generic adjuvant formulation of nonmetastatic colorectal cancer. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Enteritis as a complication of adjuvant combination chemotherapy using 5-fluorouracil and leukovorin: clinical and helical computed tomographic features. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Preoperative chemoradiotherapy with oral doxifluridine plus low-dose oral leucovorin in unresectable primary rectal cancer. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Integrated treatment with doxifluridine and radiotherapy in recurrent or primary unresectable rectal cancer. A feasibility study. [2022]