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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of combining radiation and chemotherapy for esophageal cancer patients before surgery. It seeks to determine if a mix of medications and a specialized form of radiation can kill more cancer cells while reducing side effects. The treatment uses drugs like fluorouracil and oxaliplatin, which damage cancer cell DNA and inhibit growth. Individuals with stage I-III esophageal or gastroesophageal junction cancer considering surgery may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Research has shown that the treatments in this clinical trial—fluorouracil, hypofractionated radiation therapy, leucovorin calcium, and oxaliplatin—have promising safety records.

Fluorouracil, when combined with other chemotherapy drugs, is generally safe, though some patients might experience side effects like nausea or low blood cell counts. Studies have found that combining it with leucovorin enhances its effectiveness against tumors.

Hypofractionated radiation therapy delivers higher doses of radiation over a shorter period and is well-tolerated, with side effects similar to those of traditional radiation therapy, according to research.

Leucovorin calcium often enhances the effects of fluorouracil and is usually well-tolerated. It helps reduce some harmful effects of chemotherapy.

Oxaliplatin, another chemotherapy drug in this trial, is less harmful than some other chemotherapy options, though it can cause side effects like nerve damage, leading to tingling or numbness.

Overall, these treatments have been used in various studies with manageable side effects. The trial aims to evaluate their combined effectiveness in treating esophageal cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment for esophageal cancer because it combines the power of chemotherapy with a unique approach to radiation therapy. Unlike standard treatments, which often involve prolonged radiation schedules, this trial uses hypofractionated radiation therapy, delivering higher doses over a shorter period. This method could potentially reduce treatment time and improve patient convenience. Additionally, the use of FLOT and FOLFOX regimens integrates multiple chemotherapy agents, which might enhance effectiveness by attacking the cancer cells through different mechanisms. This combination of therapies aims to offer a more aggressive and potentially more effective treatment option for patients.

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

This trial will evaluate the effectiveness of combining chemotherapy with radiation therapy for esophageal cancer. Participants will receive a combination of three drugs—fluorouracil, oxaliplatin, and leucovorin calcium—alongside hypofractionated radiation therapy. Studies have shown that fluorouracil stops cancer cells from making DNA, which they need to grow, while leucovorin enhances fluorouracil's effectiveness. Oxaliplatin damages the DNA of cancer cells, aiding in their destruction. Research indicates that using higher doses of radiation over a shorter time, known as hypofractionated radiation therapy, has shown promising results in killing more tumor cells with fewer side effects. This combination aims to improve the chances of shrinking the tumor before surgery. ^{1 2 3 5 6}

Who Is on the Research Team?

Christopher L. Hallemeier, M.D.

Principal Investigator

Mayo Clinic in Rochester

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: Treatment (FLOT and Radiation and FOLFOX) Experimental Treatment 12 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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12523764/

Real-World Effectiveness of Cisplatin, 5-Fluorouracil, and ... This study aimed to evaluate the real-world effectiveness and safety of CF plus Pem therapy and assess survival outcomes based on the initial dose intensity.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12388350/

Weekly Cisplatin and 5-Fluorouracil in Neoadjuvant ... This research evaluates the safety and efficacy of weekly cisplatin and 5-FU as outpatient neoadjuvant chemotherapy for esophageal cancer, ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.3_suppl.365

Safety and efficacy of neoadjuvant docetaxel, cisplatin, and ... Recurrence-free survival as a surrogate for overall survival in esophageal squamous cell carcinoma: Nationwide real-world data from Japan.

4. journals.plos.org journals.plos.org/plosone/article?id=10.1371/journal.pone.0326056

Efficacy and safety of cisplatin + docetaxel + 5-FU + leucovorin ... Reported response rates range from 25% to 45%, with a median overall survival of 6–10 months in phase II and III trials [11–15]. However, the outcomes remain ...

5. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/s12885-025-14011-4

Real-world safety and efficacy of neoadjuvant docetaxel ... Outcomes of preoperative chemotherapy with docetaxel, cisplatin, and 5-fluorouracil followed by esophagectomy in patients with resectable node- ...

6. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK549808/

Fluorouracil - StatPearls - NCBI Bookshelf The overall response rate of advanced colorectal cancer to fluorouracil monotherapy is only 10% to 15% and 40% to 50% when combined with other chemotherapeutic ...