Combination Chemotherapy + Radiation for Rectal Cancer

Overseen By Vincent Basehart

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Jonsson Comprehensive Cancer Center

Disqualifiers: Active malignancy, Metastatic disease, Pregnancy, others

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

Compensation: Varies

Number of Visits: 5

25 Participants Needed

Trial Summary

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 evidence supports the effectiveness of the drug combination of Capecitabine, Xeloda, Fluorouracil, and Oxaliplatin with radiation for rectal cancer?

Research shows that using Capecitabine (Xeloda) or Fluorouracil (5-FU) with radiation can effectively reduce tumor size and improve outcomes in rectal cancer. Adding Oxaliplatin to this combination may enhance these effects, although more studies are needed to confirm this. ^{1 2 3 4 5}

Is the combination of chemotherapy and radiation for rectal cancer safe for humans?

The combination of chemotherapy drugs like capecitabine (Xeloda) and 5-fluorouracil (5-FU) with radiation therapy has been shown to have a favorable safety profile in treating rectal cancer. Common side effects include hand-foot syndrome and mild, reversible leukopenia (low white blood cell count), but severe diarrhea is not common. These treatments have been well-tolerated in clinical trials, making them a generally safe option for patients. ^{1 5 6 7 8}

What makes this treatment for rectal cancer unique?

This treatment combines chemotherapy drugs like capecitabine and oxaliplatin with advanced radiation therapy (Intensity-Modulated Radiation Therapy) to potentially improve outcomes by reducing tumor size before surgery. The combination aims to enhance the effectiveness of radiation and chemotherapy, offering a promising alternative to traditional treatments. ^{1 2 3 9 10}

What is the purpose of this trial?

This phase I trial investigates how well short-course radiation therapy followed by combination chemotherapy works in treating patients with stage II-III rectal cancer. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Chemotherapy drugs, such as leucovorin, fluorouracil, oxaliplatin, 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. Giving short-course radiation therapy and combination chemotherapy may reduce the need for surgery and therefore improve quality of life.

Research Team

Ann Raldow, MD

Principal Investigator

UCLA / Jonsson Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with stage II-III rectal adenocarcinoma confirmed by lab tests, without metastatic disease. They should be in good enough health to perform daily activities (KPS >= 70 or ECOG 0-2) and have normal blood counts and liver function tests. Pregnant or breastfeeding individuals, those with other active cancers, prior radiation in the same area, or conditions preventing MRI are excluded.

Inclusion Criteria

Hemoglobin (Hgb) > 8.0 gm/dL

Platelets (PLT) > 150,000/mm^3

Total bilirubin <= 1.5 x upper limit of normal

Exclusion Criteria

I am currently being treated for another type of cancer.

Pregnant and/or breastfeeding

I've had radiation in the same area where my current cancer is located.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants undergo short-course radiation therapy in the form of intensity-modulated radiation therapy (IMRT) over 5 fractions daily for 5 consecutive days

1 week

5 visits (in-person)

Chemotherapy

Participants receive either mFOLFOX6 or CapeOX chemotherapy regimens. mFOLFOX6 is administered every 2 weeks for up to 8 cycles, and CapeOX is administered every 3 weeks for up to 6 cycles

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment. NOM patients are followed up every 3 months for 2 years, then every 6 months for 3 years. TME patients are followed up every 3-6 months for 2 years, then every 6 months for 3 years

5 years

Treatment Details

Interventions

• Capecitabine
• Fluorouracil
• Intensity-Modulated Radiation Therapy
• Leucovorin
• Oxaliplatin
• Total Mesorectal Excision

Trial Overview The study is testing if a short course of high-energy x-ray radiation followed by chemotherapy drugs like leucovorin, fluorouracil, oxaliplatin, and capecitabine can shrink tumors in rectal cancer patients without immediate surgery. The goal is to see if this approach improves quality of life by delaying or avoiding surgery.

Participant Groups

Group I: Treatment (IMRT, mFOLFOX6, CapeOX, TME) Experimental Treatment 8 Interventions

Patients undergo SCRT in the form of IMRT over 5 fractions daily for 5 consecutive days. Beginning 11-18 days after the last day of radiation therapy, patients receive either oxaliplatin IV and leucovorin IV on day 1 and fluorouracil IV on days 1-3 (mFOLFOX6) or oxaliplatin IV on day 1 and capecitabine PO BID on days 1-14 (CapeOX). Treatment with mFOLFOX6 repeats every 2 weeks for up to 8 cycles, and treatment with CapeOX repeats every 3 weeks for up to 6 cycles in the absence of disease progression or unacceptable toxicity. At 8-12 weeks after completion of all therapy, patients with residual tumor undergo TME. Patients with cCR undergo NOM.

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

Approved in European Union as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in United States as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Canada as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Japan as Xeloda for:

• Colorectal cancer
• Breast cancer

Who Is Running the Clinical Trial?

Jonsson Comprehensive Cancer Center

Lead Sponsor

Trials

373

Recruited

35,200+

The Joseph Drown Foundation

Collaborator

Trials

1

Recruited

30+

Natera, Inc.

Industry Sponsor

Trials

56

Recruited

50,700+

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]

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 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]

In a phase II study involving 54 patients with locally advanced rectal cancer, the combination of capecitabine and radiotherapy resulted in a pathologic complete response rate of 18% and a significant downstaging of tumors in 51% of patients, indicating its efficacy as a neoadjuvant treatment.

The treatment was well tolerated, with manageable side effects, and showed a sphincter preservation rate of 67% for tumors located close to the anal verge, making it a convenient alternative to traditional 5-FU infusion methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of capecitabine (Xeloda) and concomitant boost radiotherapy in patients with locally advanced rectal cancer. Krishnan, S., Janjan, NA., Skibber, JM., et al.[2022]

5-fluorouracil (5-FU) remains a key chemotherapy drug for colorectal cancer, but its oral form was previously abandoned due to inconsistent absorption; however, Xeloda (capecitabine) offers a solution by being an orally administered drug that is selectively activated in tumors, leading to higher local concentrations of 5-FU.

In phase II clinical trials for colorectal cancer, Xeloda demonstrated response rates of 21-24% and a median time to disease progression of 127-230 days, indicating its efficacy as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluoropyrimidines: a critical evaluation. Brito, RA., Medgyesy, D., Zukowski, TH., et al.[2017]

Capecitabine, an oral fluoropyrimidine, has been shown to achieve superior response rates and equivalent overall survival compared to traditional intravenous 5-FU plus leucovorin in metastatic colorectal cancer, making it a preferred treatment option.

Recent trials, including the Xeloda Adjuvant Chemotherapy Trial (X-ACT), confirm that capecitabine is at least as effective and safer than IV 5-FU/LV for adjuvant treatment in patients with resected stage III colon cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral capecitabine: bridging the Atlantic divide in colon cancer treatment. Van Cutsem, E., Verslype, C., Tejpar, S.[2018]

Preoperative radiotherapy combined with oral capecitabine has shown promising results in increasing tumor down-staging and the likelihood of sphincter-sparing surgeries, with a pathological complete response rate of up to 31% in some trials.

Capecitabine, taken orally, may offer a safer alternative to intravenous 5-fluorouracil, as it reduces the risk of complications associated with long-term venous access, although it can cause mild to moderate side effects like hand-foot syndrome and leukopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy and oral capecitabine in the preoperative treatment of patients with rectal cancer: rationale, preliminary results and perspectives. Corvò, R., Pastrone, I., Scolaro, T., et al.[2022]

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 study of 110 patients with advanced rectal cancer, the combination of preoperative radiotherapy and XELOX (capecitabine and oxaliplatin) resulted in a pathologic complete response (pCR) rate of 16%, indicating significant tumor reduction before surgery.

The treatment was generally feasible, with 95% of patients achieving R0 resections, although 43% experienced postoperative complications, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. Rödel, C., Liersch, T., Hermann, RM., et al.[2022]

In a study of 65 patients with rectal adenocarcinoma, pre-operative radiotherapy combined with oral tegafur-uracil (UFUR) and leucovorin (LV) resulted in significant tumor downstaging in 75% of patients and a pathological complete response in 25%.

The treatment showed a high 3-year overall survival rate of 92% and manageable toxicity, with only 9% of patients experiencing severe diarrhea and 3% experiencing severe leucopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-operative chemoradiotherapy with oral tegafur-uracil and leucovorin for rectal cancer. Wang, LW., Yang, SH., Lin, JK., et al.[2013]

References

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

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

2. Greece pubmed.ncbi.nlm.nih.gov

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

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

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

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

Phase II study of capecitabine (Xeloda) and concomitant boost radiotherapy in patients with locally advanced rectal cancer. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Fluoropyrimidines: a critical evaluation. [2017]

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

Oral capecitabine: bridging the Atlantic divide in colon cancer treatment. [2018]

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

Radiotherapy and oral capecitabine in the preoperative treatment of patients with rectal cancer: rationale, preliminary results and perspectives. [2022]

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

Multicenter dose-finding study of concurrent capecitabine and radiotherapy as adjuvant treatment for operable rectal cancer. [2019]

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

Multicenter phase II trial of chemoradiation with oxaliplatin for rectal cancer. [2022]

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

Pre-operative chemoradiotherapy with oral tegafur-uracil and leucovorin for rectal cancer. [2013]