Combination Therapy for Esophageal Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Case Comprehensive Cancer Center

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: 3

63 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well oxaliplatin, leucovorin calcium, and fluorouracil followed by surgery and response based concurrent chemotherapy and radiation therapy works in treating patients with cancer of the esophagus, gastroesophageal junction, or gastric cardia. Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, fluorouracil, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high energy x rays to kill tumor cells. Giving chemotherapy followed by surgery and response based chemotherapy and radiation therapy may kill more tumor cells.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have had prior chemotherapy, radiation, or surgery for this cancer, and you cannot be on any other investigational therapy.

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

Research shows that combining oxaliplatin, 5-fluorouracil, and leucovorin with radiotherapy is effective and safe for treating advanced esophageal cancer. Additionally, the combination of leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX) has been evaluated for its efficacy in treating esophageal squamous cell carcinoma after surgery. ^{1 2 3 4 5}

Is the combination therapy for esophageal cancer safe for humans?

The combination of oxaliplatin, 5-fluorouracil, and leucovorin with radiotherapy has been shown to be safe for treating locally advanced esophageal cancer in a previous study. ^{1 2 6 7 8}

What makes the combination therapy for esophageal cancer unique?

This treatment combines three drugs—fluorouracil, leucovorin, and oxaliplatin—with surgery, which is different from the more common use of fluorouracil and cisplatin. The addition of oxaliplatin and the surgical approach may offer a new option for patients, especially those who have developed resistance to standard chemotherapy. ^{1 2 3 5 9}

Research Team

Michael McNamara, MD

Principal Investigator

Case Comprehensive Cancer Center

Eligibility Criteria

This trial is for adults with specific cancers of the esophagus, gastroesophageal junction, or gastric cardia. They must be in good physical condition (ECOG 0-1), have adequate blood counts and organ function, and no severe neuropathy. Pregnant women, those with distant metastasis or another active cancer (with some exceptions), prior treatments for this cancer, certain infections like hepatitis B/C or HIV, serious heart conditions, or other medical issues that could affect participation are excluded.

Inclusion Criteria

Alkaline phosphatase ≤ 3X the institutional ULN

Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3X the institutional ULN

My cancer is a type of adenocarcinoma located in my esophagus, GEJ, or stomach.

Exclusion Criteria

My cancer diagnosis is specifically adenocarcinoma.

Patients who are pregnant or lactating will not be eligible; pregnant patients are ineligible

Patients with known infection with human immunodeficiency virus (HIV) will not be eligible

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Patients receive oxaliplatin, leucovorin calcium, and fluorouracil over 44 hours on days 1-3, repeated every 14 days for up to 4 courses

8 weeks

Surgery

Approximately 4-5 weeks after completion of induction chemotherapy, patients undergo a surgical procedure

4-5 weeks

Adjuvant Therapy

Within 6-12 weeks after surgery, patients undergo radiation therapy for 28 days. Additional chemotherapy is given based on pathological response

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 3 months for 2 years, every 4-5 months for 3 years, then annually

Treatment Details

Interventions

• Carboplatin
• Fluorouracil
• Leucovorin Calcium
• Oxaliplatin
• Paclitaxel
• Radiation Therapy
• Therapeutic Conventional Surgery

Trial Overview The study tests a combination of chemotherapy drugs (oxaliplatin, leucovorin calcium, fluorouracil) followed by surgery and then more chemo alongside radiation therapy based on how well the patient responds to initial treatment. The goal is to see if this approach is effective at stopping tumor growth by killing cells or preventing them from dividing.

Participant Groups

Group I: Negative Pathologic Response Experimental Treatment 7 Interventions

Patients with \>50% viable tumor cells remaining in the surgical specimen, will receive postoperative chemo-radiotherapy with weekly carboplatin and paclitaxel.

Group II: Positive Pathologic Response Active Control 5 Interventions

Patients with ≤50% viable tumor cells remaining in the surgical specimen will receive postoperative chemo-radiotherapy with the mFOLFOX6 regimen

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?

Case Comprehensive Cancer Center

Lead Sponsor

Trials

472

Recruited

33,400+

Findings from Research

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]

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 phase II study involving 50 patients with advanced oesophageal cancer, the addition of cetuximab to the standard treatment of 5-FU/cisplatin/docetaxel (TPF) and chemoradiotherapy resulted in a clinical complete response (cCR) rate of 12% and an overall response rate of 54%.

The median overall survival for patients who underwent complete surgical resection was significantly longer at 42.1 months compared to 24.9 months for those who did not have surgery, indicating that achieving a complete resection is crucial for improving survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II Study Evaluating Combined Neoadjuvant Cetuximab and Chemotherapy Followed by Chemoradiotherapy and Concomitant Cetuximab in Locoregional Oesophageal Cancer Patients. Alsina, M., Rivera, F., Ramos, FJ., et al.[2019]

In a study of 35 patients with advanced esophageal cancer, the combination of oxaliplatin, leucovorin, and fluorouracil demonstrated a 40% overall response rate, indicating significant anti-tumor activity.

While the treatment was effective, it also had notable side effects, including a 29% incidence of severe neutropenia and 26% experiencing significant peripheral neuropathy, highlighting the need for careful monitoring of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus. Mauer, AM., Kraut, EH., Krauss, SA., et al.[2020]

In a study involving 42 patients with metastatic colorectal cancer, the combination of 5-fluorouracil (5-FU) and sodium folinate (S-FA) administered via a continuous 24-hour infusion was found to be a safe and effective second-line treatment, achieving a 9% objective response rate and halting tumor progression in 74% of patients.

The treatment resulted in a median survival of 14.7 months and a median time to tumor progression of 5.7 months, with manageable side effects including grade III/IV diarrhea in 19% of patients, indicating that the new formulation allows for convenient simultaneous administration of both drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-line treatment of advanced colorectal cancer with a weekly simultaneous 24-hour infusion of 5-fluorouracil and sodium-folinate: a multicentre phase II trial. Kuhfahl, J., Steinbrecher, C., Wagner, T., et al.[2013]

In a study of 51 patients with metastatic colorectal cancer, the combination of 5-fluorouracil (5-FU) and sodium-folinic acid (S-FA) resulted in a 37.2% objective response rate, with 3.9% achieving complete remission and 33.3% showing partial remission.

The treatment demonstrated a median survival of 16.5 months and a median time to tumor progression of 8.5 months, with manageable toxicity levels, making S-FA a convenient and effective option for outpatient therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of a weekly 24-hour infusion with 5-fluorouracil and simultaneous sodium-folinic acid in the first-line treatment of metastatic colorectal cancer. Hartung, G., Hofheinz, RD., Wein, A., et al.[2017]

In a study of 30 patients with resectable esophageal squamous cell carcinoma, a chemotherapy regimen combining 5-fluorouracil, cisplatin, and interferon-alpha showed promising results, with a median overall survival of 26.3 months.

The treatment led to a complete pathological response in 4 out of 23 patients who underwent esophagectomy, indicating significant effectiveness, although there was one toxic death due to esophageal perforation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of neoadjuvant cisplatin, 5-fluorouracil and interferon-alpha in operable squamous cell carcinoma of the esophagus. Bazarbashi, S., Abdelsalam, M., Amin, T., et al.[2013]

References

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

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

2. Korea (South) pubmed.ncbi.nlm.nih.gov

A Randomized Phase II Study of Leucovorin/5-Fluorouracil with or without Oxaliplatin (LV5FU2 vs. FOLFOX) for Curatively-Resected, Node-Positive Esophageal Squamous Cell Carcinoma. [2018]

3. Greece pubmed.ncbi.nlm.nih.gov

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

4. France pubmed.ncbi.nlm.nih.gov

A phase II Study Evaluating Combined Neoadjuvant Cetuximab and Chemotherapy Followed by Chemoradiotherapy and Concomitant Cetuximab in Locoregional Oesophageal Cancer Patients. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Phase II trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus. [2020]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Second-line treatment of advanced colorectal cancer with a weekly simultaneous 24-hour infusion of 5-fluorouracil and sodium-folinate: a multicentre phase II trial. [2013]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Phase II study of a weekly 24-hour infusion with 5-fluorouracil and simultaneous sodium-folinic acid in the first-line treatment of metastatic colorectal cancer. [2017]

8. England pubmed.ncbi.nlm.nih.gov

Drug interactions of 5-fluorouracil with either cisplatin or lobaplatin--a new, clinically active platinum analog in established human cancer cell lines. [2019]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Phase II trial of neoadjuvant cisplatin, 5-fluorouracil and interferon-alpha in operable squamous cell carcinoma of the esophagus. [2013]