Radiotherapy + Chemotherapy for Esophageal Cancer

(PHOX Trial)

Recruiting at 2 trial locations

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Mayo Clinic

Disqualifiers: Metastatic disease, Upper esophageal tumor, Prior chemotherapy, 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: 26

99 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

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

What data supports the effectiveness of the treatment Radiotherapy + Chemotherapy for Esophageal Cancer?

Research shows that 5-Fluorouracil (5-FU) combined with radiotherapy has been used to improve tumor control in esophageal cancer, and the combination of 5-FU and cisplatin is commonly used for this condition. Additionally, fluorinated pyrimidines, like 5-FU, are known to enhance the effects of radiotherapy, making them effective in treating esophageal cancer. ^{1 2 3 4 5}

Is the combination of radiotherapy and chemotherapy safe for esophageal cancer?

The combination of oxaliplatin, 5-fluorouracil, and leucovorin with radiotherapy has been shown to be safe for treating locally advanced esophageal cancer. Another study found that using docetaxel and 5-fluorouracil with radiotherapy was also safe, with mild blood-related side effects and some cases of esophagitis (inflammation of the esophagus). ^{6 7 8 9 10}

How is the treatment of Radiotherapy + Chemotherapy for Esophageal Cancer unique?

This treatment combines oxaliplatin, 5-fluorouracil, and leucovorin with hypofractionated radiotherapy, which is a novel approach compared to the more common use of cisplatin with 5-fluorouracil. The use of oxaliplatin and hypofractionated radiotherapy may offer a different safety and efficacy profile for patients with locally advanced esophageal cancer. ^{2 3 4 6 7}

What is the purpose of this trial?

This phase II trial tests how well preoperative (prior to surgery) radiation therapy with fluorouracil, oxaliplatin, and leucovorin calcium (FOLFOX) works for the treatment of stage I-III esophageal or gastroesophageal junction adenocarcinoma. Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter period of time and may kill more tumor cells and have fewer side effects. Fluorouracil stops cells from making deoxyribonucleic acid (DNA) and it may kill tumor cells. Leucovorin is not a chemotherapy medication but is given in conjunction with chemotherapy. Leucovorin is used with the chemotherapy medication fluorouracil to enhance the effects of the fluorouracil, in other words, to make the drug work better. Oxaliplatin is in a class of medications called platinum-containing antineoplastic agents. It damages the cell's DNA and may kill tumor cells. Giving preoperative hypofractionated radiation with fluorouracil and oxaliplatin may kill more tumor cells in patients with stage I-III esophageal or gastroesophageal junction adenocarcinoma.

Research Team

Christopher L. Hallemeier, M.D.

Principal Investigator

Mayo Clinic in Rochester

Eligibility Criteria

This trial is for adults with stage I-III esophageal or gastroesophageal junction adenocarcinoma confirmed by biopsy, who are fit for surgery and have not had prior chemo or radiotherapy to the chest. Participants must be able to consent, complete questionnaires, provide blood samples for research, and use effective contraception if of childbearing potential.

Inclusion Criteria

You are willing to donate blood samples for correlative research.

My cancer is confirmed as esophageal or gastroesophageal junction adenocarcinoma, at a specific stage.

A surgeon has approved me for esophagus surgery.

Exclusion Criteria

I am currently breastfeeding.

My cancer is located in my cervix or upper esophagus.

Co-morbid systemic illnesses or other severe concurrent disease which, in the judgement of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with proper assessment of adverse events

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction Chemotherapy

Patients receive FLOT (5-FU/leucovorin/oxaliplatin/docetaxel) every 2 weeks for up to 4 cycles

8 weeks

4 visits (in-person)

Radiation and Concurrent Chemotherapy

Patients undergo radiation therapy daily for 3 weeks with 2 concurrent cycles of FOLFOX

6 weeks

15 visits (in-person) for radiation, 3 visits (in-person) for chemotherapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Follow-up at 6, 12, and 24 months, then annually up to 5 years

Treatment Details

Interventions

• Fluorouracil
• Hypofractionated Radiation Therapy
• Leucovorin Calcium
• Oxaliplatin

Trial Overview The study tests preoperative hypofractionated radiation therapy combined with FOLFOX (fluorouracil, oxaliplatin, leucovorin calcium) in treating esophageal cancer. The goal is to see if this approach kills more tumor cells before surgery compared to standard treatments.

Participant Groups

Group I: Treatment (FLOT and Radiation and FOLFOX) Experimental Treatment 11 Interventions

Patients received Induction Chemotherapy \[FLOT (5-FU/leucovorin/oxaliplatin/docetaxel)\] following by radiation therapy daily for 3 weeks with 2 concurrent cycles of FOLFOX per protocol. See detailed description for more information.

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?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a Phase I study involving 10 patients with resectable esophageal cancer, the maximal tolerated dose of the oral chemotherapy UFT was determined to be 200 mg/m²/day, which was associated with manageable toxicity, primarily nausea.

The combination of UFT, leucovorin, and cisplatin with radiotherapy resulted in downstaging of the disease in 6 out of 8 patients who underwent surgery, indicating potential efficacy in treating esophageal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial of Orzel (UFT plus leucovorin), cisplatin, and radiotherapy in the treatment of potentially resectable esophageal cancer. Tedesco, KL., Berlin, J., Blanke, CD., et al.[2013]

The study established a 5-Fluorouracil (5-FU) and cisplatin-resistant xenograft model in SCID mice to investigate the mechanisms behind acquired resistance in esophageal cancer treatment.

Gene expression analysis revealed that resistance to FP chemotherapy is linked to the activation of specific genes related to 5-FU and cisplatin, as well as the PI3K/AKT signaling pathway, suggesting potential targets for overcoming resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene expression changes in a chemoresistant model with human esophageal cancer xenografts using cDNA microarray. Yoshida, T., Miyoshi, T., Seike, J., et al.[2015]

In a pilot trial involving 32 patients with locoregional esophageal carcinoma, the combination of continuous infusion 5-fluorouracil (CI5-FU), cisplatin, and radiotherapy resulted in a complete response in 44% of patients and a median survival of 20 months, with a 1-year survival rate of 59%.

Despite the promising efficacy, the treatment regimen was associated with severe toxicity, including esophagitis and gastrointestinal complications, leading to dose reductions and early deaths, indicating that modifications are necessary for safer application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of multimodality treatment of locoregional esophageal carcinoma by Southwest Oncology Group 9060. Poplin, EA., Jacobson, J., Herskovic, A., et al.[2013]

In a phase II trial involving 40 patients with advanced esophageal cancer, a treatment regimen using paclitaxel and cisplatin with accelerated radiation resulted in higher toxicity, including more cases of severe leukopenia and unplanned hospitalizations, compared to previous treatments with fluorouracil (5-FU).

Despite the increased toxicity, the paclitaxel-based regimen did not show any improvement in survival rates or disease control compared to the 5-FU treatment, indicating that further research is needed before adopting paclitaxel as a standard treatment for esophageal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does paclitaxel improve the chemoradiotherapy of locoregionally advanced esophageal cancer? A nonrandomized comparison with fluorouracil-based therapy. Adelstein, DJ., Rice, TW., Rybicki, LA., et al.[2022]

A regimen of accelerated hyperfractionated radiotherapy combined with low-dose cisplatin and continuous infusion fluorouracil showed effectiveness in treating locally advanced squamous cell carcinoma of the esophagus, resulting in a median survival of 28 months and a 5-year survival rate of 38%.

Patients who achieved a pathological complete response had significantly better outcomes, with a median survival of 132 months and a 5-year survival rate of 72%, indicating the importance of treatment response in predicting long-term survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative low-dose weekly cisplatin and continuous infusion fluorouracil plus hyperfractionated radiotherapy in stage II-III esophageal carcinoma. Caro, M., Font, A., Comas, S., et al.[2019]

The maximum tolerated dose (MTD) of S-1, an oral 5-FU derivative, was determined to be 80 mg/m², with a recommended dose of 70 mg/m² for further studies, indicating a safe dosing range for elderly patients with esophageal cancer.

The treatment regimen showed promising efficacy, with an endoscopic complete response in 66.7% of patients, a median progression-free survival of 20 months, and a median overall survival of 29 months, suggesting that S-1 combined with radiotherapy is an effective option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I dose escalation study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer. Ji, Y., Qiu, G., Sheng, L., et al.[2022]

The combination of oxaliplatin, 5-fluorouracil, and leucovorin with concurrent radiotherapy was found to be safe and effective for treating locally advanced esophageal carcinoma, with 42 patients showing promising results in a structured treatment regimen.

Patients who received preoperative concurrent chemoradiotherapy had a median survival of 28 months, with significant down-staging observed in 16 out of 24 patients, indicating the potential for improved outcomes with this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent oxaliplatin, 5-fluorouracil, and radiotherapy in the treatment of locally advanced esophageal carcinoma. O'Connor, BM., Chadha, MK., Pande, A., et al.[2018]

In a phase II study involving 16 patients with inoperable locally advanced esophageal squamous cell carcinoma, the chemoradiotherapy regimen using docetaxel and 5-fluorouracil showed a high response rate of 94%, with 31% achieving complete response.

The treatment was found to be safe, with mild hematologic toxicity and manageable nonhematologic side effects, leading to a median progression-free survival of 20 months and 3-year and 5-year survival rates of 44% and 31%, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of definitive chemoradiotherapy using docetaxel and 5-fluorouracil in patients with unresectable locally advanced esophageal squamous cell carcinoma: a phase II study. Hihara, J., Hamai, Y., Emi, M., et al.[2022]

In a phase 2 study involving 42 patients with advanced esophageal cancer, the combination of docetaxel, cisplatin, and 5-fluorouracil (DCF-R) showed a clinical complete response rate of 52.4%, indicating significant efficacy in treating this condition.

While DCF-R was effective, it also led to considerable side effects, including high rates of leukopenia and neutropenia, suggesting that while the treatment is promising, careful monitoring for these toxicities is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Definitive chemoradiation therapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) in advanced esophageal cancer: a phase 2 trial (KDOG 0501-P2). Higuchi, K., Komori, S., Tanabe, S., et al.[2022]

In a Phase II trial involving 30 elderly patients with esophageal cancer, concurrent chemoradiotherapy (CCRT) using S-1 demonstrated a 2-year overall survival rate of 45.1%, surpassing the target of 35%.

The treatment was associated with mild toxicity, with no grade 4 toxicities or treatment-related deaths, indicating that S-1 may be a safer alternative to conventional platinum-based therapies for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer. Ji, Y., Du, X., Tian, Y., et al.[2022]

References

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

Phase I trial of Orzel (UFT plus leucovorin), cisplatin, and radiotherapy in the treatment of potentially resectable esophageal cancer. [2013]

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

Gene expression changes in a chemoresistant model with human esophageal cancer xenografts using cDNA microarray. [2015]

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

Evaluation of multimodality treatment of locoregional esophageal carcinoma by Southwest Oncology Group 9060. [2013]

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

Does paclitaxel improve the chemoradiotherapy of locoregionally advanced esophageal cancer? A nonrandomized comparison with fluorouracil-based therapy. [2022]

5. Italy pubmed.ncbi.nlm.nih.gov

Preoperative low-dose weekly cisplatin and continuous infusion fluorouracil plus hyperfractionated radiotherapy in stage II-III esophageal carcinoma. [2019]

6. China pubmed.ncbi.nlm.nih.gov

A phase I dose escalation study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer. [2022]

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

Concurrent oxaliplatin, 5-fluorouracil, and radiotherapy in the treatment of locally advanced esophageal carcinoma. [2018]

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

Role of definitive chemoradiotherapy using docetaxel and 5-fluorouracil in patients with unresectable locally advanced esophageal squamous cell carcinoma: a phase II study. [2022]

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

Definitive chemoradiation therapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) in advanced esophageal cancer: a phase 2 trial (KDOG 0501-P2). [2022]

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

A phase II study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer. [2022]