Chemotherapy + Radiation for Esophageal Cancer

Recruiting at 9 trial locations

Overseen By Kebron Elias

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Colorado, Denver

Disqualifiers: Metastatic cancer, Squamous carcinoma, Prior malignancy, others

Stay on Your Current Meds You can continue your current medications while participating

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This study evaluates a novel regimen of induction chemotherapy using a combination of docetaxel, oxaliplatin, and leucovorin, with short term infusional 5-FU (FLOT), given prior to chemoradiotherapy with concurrent carboplatin and paclitaxel, as neoadjuvant therapy prior to definitive surgical resection for patients with adenocarcinoma of the esophagus or gastroesophageal junction

Do I need to stop my current medications to join the trial?

The protocol does not specify if you need to stop your current medications. However, since the trial involves chemotherapy and radiation, it's possible that some medications might need to be adjusted. Please consult with the trial coordinators for specific guidance.

What data supports the idea that Chemotherapy + Radiation for Esophageal Cancer is an effective treatment?

The available research shows that Chemotherapy + Radiation, specifically the CROSS regimen, is effective for treating esophageal cancer. It achieves a good local response, with up to 33% of patients experiencing a complete response, meaning the cancer is no longer detectable. When compared to the FLOT regimen, which is another chemotherapy approach, CROSS is noted for its effectiveness in managing locally advanced esophageal cancer. Additionally, the FLOT regimen is highlighted for improving survival rates in patients with esophagogastric cancer, suggesting that both treatments have their strengths in different aspects of cancer management. ^{1 2 3 4 5}

What safety data exists for chemotherapy and radiation treatment for esophageal cancer?

The safety data for chemotherapy and radiation treatment, including regimens like FLOT and CROSS, show varying levels of toxicity. The FLOT regimen, which includes 5-FU, leucovorin, oxaliplatin, and docetaxel, is noted for its effectiveness but also for significant toxicity, with up to 50-70% of patients experiencing grade 3-4 neutropenia. The CROSS regimen, used for neoadjuvant chemoradiotherapy, achieves good locoregional response rates. A phase II study of definitive chemoradiotherapy using docetaxel and 5-fluorouracil reported mild hematologic toxicity and some nonhematologic adverse events like esophagitis and anorexia, but no treatment-related deaths. Overall, while these treatments are effective, they are associated with notable toxicities, and further trials are needed to develop less toxic strategies. ^{1 3 4 6 7}

Is Sequential FLOT a promising drug for esophageal cancer?

Yes, Sequential FLOT is a promising drug for esophageal cancer. It has shown superior results in treating non-metastatic esophagogastric cancer compared to other treatments. It is effective in improving patient survival and reducing cancer recurrence. ^{1 2 3 4 8}

Research Team

Jeffrey Olsen, M.D.

Principal Investigator

University of Colorado, Denver

Eligibility Criteria

This trial is for adults with newly diagnosed, resectable esophageal or gastroesophageal junction adenocarcinoma who haven't had chemotherapy or radiation. They must be fit enough for triple therapy (chemo, radiation, surgery), have proper kidney and liver function, and not be pregnant. Contraception is required during the study.

Inclusion Criteria

I am a woman who can have children, have a negative pregnancy test, and will use birth control during and 3 months after the study.

My kidney function, measured by creatinine levels, is within the normal range.

My kidney function, based on a formula considering my age, weight, and creatinine levels, is adequate.

Exclusion Criteria

I have a history of hepatitis B or C.

I have no allergies or adverse reactions to the chemotherapy drugs used in this study.

Pregnant or breast-feeding women.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Participants receive induction chemotherapy using a combination of docetaxel, oxaliplatin, leucovorin, and short-term infusional 5-FU (FLOT)

8-12 weeks

Neoadjuvant Chemoradiation

Participants undergo chemoradiotherapy with concurrent carboplatin and paclitaxel as neoadjuvant therapy

5-6 weeks

Surgical Resection

Definitive surgical resection is performed for patients with adenocarcinoma of the esophagus or gastroesophageal junction

Follow-up

Participants are monitored for safety and effectiveness after treatment, including evaluation of pathologic complete response and survival outcomes

5 years

Treatment Details

Interventions

• Chemoradiation
• Sequential FLOT

Trial Overview The trial tests a new treatment sequence starting with FLOT chemotherapy (docetaxel, oxaliplatin, leucovorin, 5-FU) followed by chemoradiation using carboplatin and paclitaxel before surgical removal of the cancer.

Participant Groups

Group I: Sequential FLOT followed by chemoradiation Experimental Treatment 1 Intervention

Sequential Chemotherapy with Docetaxel, Oxaliplatin, and 5-Fluorouracil/Leucovorin followed by chemoradiation with concurrent carboplatin and paclitaxel

Sequential FLOT is already approved in European Union, United States for the following indications:

Approved in European Union as FLOT for:

• Esophageal adenocarcinoma
• Gastroesophageal junction adenocarcinoma

Approved in United States as FLOT for:

• Locally advanced esophageal adenocarcinoma

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

American Cancer Society, Inc.

Collaborator

Trials

237

Recruited

110,000+

Cancer League of Colorado

Collaborator

Trials

13

Recruited

450+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

The CROSS protocol for chemoradiotherapy resulted in a significantly higher rate of complete pathological response in patients with distal esophageal and gastroesophageal junction tumors compared to the FLOT regimen, with 32% of CROSS patients achieving complete response versus none in the FLOT group.

Both CROSS and FLOT protocols provided similar two-year survival rates for patients with gastroesophageal junction adenocarcinoma, but the CROSS group experienced significantly more neutropenia, indicating a higher risk of hematological side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CROSS or FLOT in Distal Esophageal and Gastroesophageal Cancer. Karadag, I., Karakaya, S., Ates, O., et al.[2021]

In a study of 222 patients with locally advanced esophageal adenocarcinoma, both the FLOT and CROSS treatment regimens showed similar survival rates (around 60-63%) but differed in tolerance and side effects, with only 40% of patients completing the FLOT regimen compared to 92% for CROSS.

While both regimens had comparable operative outcomes, the CROSS regimen was associated with a higher risk of postoperative respiratory failure (13% vs. 3% for FLOT), suggesting that caution is needed when using CROSS in patients with pre-existing respiratory issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CROSS Versus FLOT Regimens in Esophageal and Esophagogastric Junction Adenocarcinoma: A Propensity-Matched Comparison. Donlon, NE., Moran, B., Kamilli, A., et al.[2022]

This phase-II study aims to evaluate the safety and feasibility of a combined FLOT and CROSS treatment regimen in 20 patients with oligometastatic esophageal adenocarcinoma, focusing on whether patients can tolerate the full treatment course.

If the FLOT-CROSS regimen is well-tolerated, it may lead to further testing in larger phase-III trials for neoadjuvant treatment in patients with locally advanced non-metastatic esophageal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy aNd chemoradiotherapy for adenocarcinoma of the OESophagus and esophagogastric junction with oligometastases: Protocol of the TNT-OES-1 trial. van der Zijden, CJ., Eyck, BM., van der Gaast, A., et al.[2023]

In a study of 277 patients with non-metastatic esophagogastric cancer treated with the FLOT protocol, the median survival was 61 months, and the postoperative in-hospital mortality rate was low at 2%.

Recurrence after treatment predominantly occurred within the first 24 months, with gastric cancer mostly recurring as peritoneal carcinomatosis (56%) and esophageal cancer as distant organ metastasis (78%), but the site of recurrence did not affect overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pattern of Recurrence and Patient Survival after Perioperative Chemotherapy with 5-FU, Leucovorin, Oxaliplatin and Docetaxel (FLOT) for Locally Advanced Esophagogastric Adenocarcinoma in Patients Treated Outside Clinical Trials. Glatz, T., Verst, R., Kuvendjiska, J., et al.[2020]

In a study comparing perioperative FLOT chemotherapy to the ECX/ECF regimen in patients with resectable oesophagogastric adenocarcinoma, FLOT was associated with a shorter median hospital stay after surgery (12 days vs. 15 days, P=0.035).

Both FLOT and ECX/ECF showed similar rates of overall perioperative complications and specific complications like anastomotic leaks, indicating that FLOT is as safe as the traditional ECX/ECF regimen for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of perioperative FLOT versus ECF/ECX on short-term outcomes after surgery for resectable oesophagogastric adenocarcinoma: propensity score-matched study. Moussa, O., Bhogal, RH., Malietzis, G., et al.[2022]

The FLOT regimen for treating esophagogastric tumors shows similar efficacy to other docetaxel-based regimens in terms of pathological complete response, resection rate, and survival outcomes, based on a meta-analysis of 16 studies involving over 1,000 patients.

Despite comparable effectiveness, the docetaxel regimens are associated with high toxicity rates, with 50-70% of patients experiencing severe neutropenia, highlighting the need for future trials to develop less toxic treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic review and meta-analysis of docetaxel perioperative chemotherapy regimens in gastric and esophagogastric tumors. Uson Junior, PLS., Santos, VM., Bugano, DDG., et al.[2021]

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 study of 593 patients with esophagogastric adenocarcinomas, the modified FLOT (mFLOT) regimen showed significantly better 3-year event-free survival (60%) compared to the EOX regimen (39%), indicating mFLOT's superior efficacy as perioperative therapy.

While mFLOT improved resection rates (86% vs. 76% for EOX), it was associated with a higher incidence of severe neutropenia and febrile neutropenia, suggesting that while mFLOT is more effective, it also carries a risk of increased toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative Modified FLOT Versus EOX in Locally Advanced Resectable Gastric and Gastro-Oesophageal Junction Adenocarcinoma: Results of a Matched-Pair Analysis. Ramaswamy, A., Bhargava, P., Srinivas, S., et al.[2023]

References

1. Pakistan pubmed.ncbi.nlm.nih.gov

CROSS or FLOT in Distal Esophageal and Gastroesophageal Cancer. [2021]

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

CROSS Versus FLOT Regimens in Esophageal and Esophagogastric Junction Adenocarcinoma: A Propensity-Matched Comparison. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Chemotherapy aNd chemoradiotherapy for adenocarcinoma of the OESophagus and esophagogastric junction with oligometastases: Protocol of the TNT-OES-1 trial. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Pattern of Recurrence and Patient Survival after Perioperative Chemotherapy with 5-FU, Leucovorin, Oxaliplatin and Docetaxel (FLOT) for Locally Advanced Esophagogastric Adenocarcinoma in Patients Treated Outside Clinical Trials. [2020]

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

Effect of perioperative FLOT versus ECF/ECX on short-term outcomes after surgery for resectable oesophagogastric adenocarcinoma: propensity score-matched study. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Systematic review and meta-analysis of docetaxel perioperative chemotherapy regimens in gastric and esophagogastric tumors. [2021]

7. 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]

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

Perioperative Modified FLOT Versus EOX in Locally Advanced Resectable Gastric and Gastro-Oesophageal Junction Adenocarcinoma: Results of a Matched-Pair Analysis. [2023]