Propranolol + Chemoradiation for Esophageal Cancer

Overseen By ASK RPCI

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Roswell Park Cancer Institute

Must be taking: Beta-blockers

Must not be taking: Calcium channel blockers

Disqualifiers: Uncontrolled diabetes, Severe asthma, 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 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 4-6 weeks

106 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the side effects and best dose of propranolol when administered concurrently with SOC neoadjuvant CRT in patients with esophageal carcinoma, with a safety lead-in and dose expansion cohort. Patients who are already on β-blockers will receive standard of care CRT and will be considered separately as a single arm prospective cohort

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but if you are already on beta-blockers, you will continue with standard care and be part of a separate group. If you are taking certain medications like calcium channel blockers or rhythm control agents, you may not be eligible to participate.

Is propranolol generally safe for use in humans?

Propranolol, a common medication for heart-related conditions, can cause some side effects like skin reactions and slow heart rate. In rare cases, an overdose can lead to severe low blood pressure and other serious symptoms. ^{1 2 3 4 5}

How does the drug propranolol combined with chemoradiation differ from other treatments for esophageal cancer?

Propranolol combined with chemoradiation for esophageal cancer is unique because it involves the use of propranolol, a beta-blocker typically used for heart conditions, alongside traditional cancer treatments. This combination may offer a novel approach by potentially enhancing the effectiveness of chemoradiation, although specific details on its efficacy for esophageal cancer are not provided in the available research. ^{6 7 8 9 10}

Research Team

Anurag K. Singh

Principal Investigator

Roswell Park Cancer Institute

Eligibility Criteria

This trial is for adults with esophageal adenocarcinoma who can swallow pills or have a feeding tube, are not pregnant, agree to use birth control, and have an ECOG performance status of 0-1. Excluded are those with severe heart issues, uncontrolled illnesses, certain psychiatric conditions, or on specific heart medications.

Inclusion Criteria

Participants of child-bearing potential must have a negative pregnancy test at study entry and then agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

I am fully active and can carry on all my pre-disease activities without restriction.

I can swallow pills or have a feeding tube for medication.

Exclusion Criteria

I do not have conditions that prevent me from using beta-blockers.

Pregnant or nursing female participants

I do not have any severe illnesses or heart problems that would stop me from following the study's requirements.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive propranolol and undergo chemoradiation therapy for esophageal cancer

4-6 weeks

5 visits per week (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Treatment Details

Interventions

• Propranolol

Trial Overview The study tests the safety and optimal dose of propranolol alongside standard chemoradiation therapy (CRT) in treating esophageal carcinoma. It includes patients already on β-blockers receiving standard CRT as a separate group for comparison.

Participant Groups

Group I: Chemoradiation Therapy plus Propanolol Experimental Treatment 3 Interventions

Patients undergo radiation therapy as in Group I. Patients receive propranolol PO BID for 4-6 weeks while receiving CRT in the absence of disease progression or unacceptable toxicity.

Group II: Chemoradiation Therapy - Group I Active Control 4 Interventions

Patients receiving beta-blockers undergo radiation therapy in the form of IMRT or 3D CRT over 23-28 fractions for 5 days per week (Monday-Friday) for 5 weeks, and receive paclitaxel IV QW and carboplatin IV QW for 5 weeks in the absence of disease progression or unacceptable toxicity.

Group III: Chemoradiation Therapy - Group II Active Control 1 Intervention

Patients undergo CRT as in Group I in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

Roswell Park Cancer Institute

Lead Sponsor

Trials

427

Recruited

40,500+

Findings from Research

The study analyzed data from the Canadian Adverse Drug Reaction Monitoring Program to assess the potential link between propranolol hydrochloride and bradycardia, finding that the signals for bradycardia were not statistically significant despite some high calculated statistics.

Although the results did not confirm a strong association between propranolol and bradycardia, the authors suggest that further investigation using larger databases is warranted due to the observed trends.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic class-specific signal detection of bradycardia associated with propranolol hydrochloride. Gavali, DK., Kulkarni, KS., Kumar, A., et al.[2021]

In a study involving 64 male nude mice with gastric cancer, propranolol was found to enhance the effectiveness of radiotherapy, resulting in reduced tumor growth compared to other treatment groups.

The combination of propranolol and radiation therapy led to decreased expression of NF-κB and its downstream targets (COX-2, EGFR, and VEGF), suggesting a mechanism by which propranolol acts as a radiosensitizer in gastric cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of propranolol as a radiosensitizer in gastric cancer treatment. Liao, X., Chaudhary, P., Qiu, G., et al.[2022]

Long-acting propranolol (Inderal LA) provides a controlled release of the medication, maintaining higher plasma concentrations over 24 hours compared to conventional tablets, which helps ensure consistent beta-adrenoceptor blockade.

This formulation is equally effective for treating conditions like angina pectoris, hypertension, and hyperthyroidism, while potentially improving patient adherence to treatment due to simplified dosing regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-acting propranolol (Inderal LA): pharmacokinetics, pharmacodynamics and therapeutic use. Mishriki, AA., Weidler, DJ.[2019]

A 21-year-old student experienced severe hypotension and respiratory depression after ingesting a dangerous combination of 6.4 g of propranolol, 280 mg of amlodipine, and 560 mg of olanzapine, highlighting the risks of mixed overdoses.

The patient was successfully treated with a combination of IntraLipid infusion, high-dose insulin, and inotropes, along with endoscopy to remove a drug bezoar, suggesting that this approach may be effective for similar overdose cases in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Too many pills to swallow: A case of a mixed overdose. Hopkins, LE., Sunkersing, J., Jacques, A.[2020]

Propranolol, a common medication used to treat various conditions, can cause rare skin reactions, including an ulcerative lichenoid drug eruption, as seen in this case.

This specific adverse reaction on the penis has not been previously documented, highlighting the need for awareness of potential side effects associated with propranolol therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lichenoid drug eruption secondary to propranolol. Massa, MC., Jason, SM., Gradini, R., et al.[2013]

The preoperative treatment regimen of cisplatin, paclitaxel, and radiation was well tolerated by 69 patients with locoregional esophageal carcinoma, with only 13% experiencing severe neutropenia and 17% requiring feeding tubes.

Ninety percent of patients achieved complete tumor resection, and the median survival was 24 months, with 1-, 2-, and 3-year survival rates of 75%, 50%, and 34%, indicating promising efficacy for this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent cisplatin, paclitaxel, and radiotherapy as preoperative treatment for patients with locoregional esophageal carcinoma. Urba, SG., Orringer, MB., Ianettonni, M., et al.[2022]

In a study of 14 patients with localized esophageal cancer, a regimen combining weekly oxaliplatin and continuous infusion of 5-fluorouracil resulted in a median overall survival of 32.6 months and a median progression-free survival of 31.5 months, indicating potential effectiveness in achieving durable remissions.

However, the treatment was associated with high rates of severe non-hematologic toxicity, including one treatment-related death, suggesting that this regimen is not suitable for routine use and that future studies should consider using lower doses of chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of chemoradiation therapy with weekly oxaliplatin and protracted infusion of 5-fluorouracil for esophageal cancer. Burmeister, BH., Walpole, ET., D'Arcy, N., et al.[2018]

In a randomized clinical trial involving 321 patients with esophageal squamous cell carcinoma (ESCC), the overall survival rates after 3 years were similar across three treatment regimens: paclitaxel with fluorouracil (57.2%), cisplatin (60.1%), and carboplatin (56.5%), indicating no significant superiority of one regimen over the others.

The cisplatin regimen was associated with significantly higher rates of severe side effects, including neutropenia (60.8%), thrombocytopenia (13.1%), and gastrointestinal issues, compared to the fluorouracil and carboplatin groups, suggesting that while all regimens are effective, cisplatin may pose greater risks for adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of 3 Paclitaxel-Based Chemoradiotherapy Regimens for Patients With Locally Advanced Esophageal Squamous Cell Cancer: A Randomized Clinical Trial. Ai, D., Ye, J., Wei, S., et al.[2022]

In a study of 41 patients with esophageal cancer, the combination of paclitaxel, cisplatin, and concurrent radiation resulted in a 29% complete response rate, indicating its efficacy in treating this type of cancer.

The treatment was associated with manageable toxicity, with only 24% of patients experiencing severe neutropenia and 5% suffering from severe esophagitis, suggesting that the regimen is relatively safe and does not require additional feeding support.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel, cisplatin, and concurrent radiation for esophageal cancer. Safran, H., Gaissert, H., Akerman, P., et al.[2019]

In a study of 34 patients with inoperable esophageal cancer, the combination of external radiotherapy and intraluminal radiotherapy (ILRT) significantly improved dysphagia in 66% of patients, demonstrating its efficacy as a palliative treatment.

The median survival for all patients was 8 months, with 26% surviving beyond 1 year, indicating that this combination therapy can provide meaningful survival benefits, although 38% experienced radiation-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience with intraluminal radiotherapy in advanced oesophageal cancer. Mohanti, BK., Shukla, NK., Chawla, S., et al.[2013]

References

1. India pubmed.ncbi.nlm.nih.gov

Therapeutic class-specific signal detection of bradycardia associated with propranolol hydrochloride. [2021]

2. New Zealand pubmed.ncbi.nlm.nih.gov

The role of propranolol as a radiosensitizer in gastric cancer treatment. [2022]

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

Long-acting propranolol (Inderal LA): pharmacokinetics, pharmacodynamics and therapeutic use. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Too many pills to swallow: A case of a mixed overdose. [2020]

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

Lichenoid drug eruption secondary to propranolol. [2013]

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

Concurrent cisplatin, paclitaxel, and radiotherapy as preoperative treatment for patients with locoregional esophageal carcinoma. [2022]

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

A phase II trial of chemoradiation therapy with weekly oxaliplatin and protracted infusion of 5-fluorouracil for esophageal cancer. [2018]

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

Comparison of 3 Paclitaxel-Based Chemoradiotherapy Regimens for Patients With Locally Advanced Esophageal Squamous Cell Cancer: A Randomized Clinical Trial. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Paclitaxel, cisplatin, and concurrent radiation for esophageal cancer. [2019]

10. India pubmed.ncbi.nlm.nih.gov

Experience with intraluminal radiotherapy in advanced oesophageal cancer. [2013]