d-Limonene + Radiation + Chemo for Dry Mouth Prevention in Head and Neck Cancer

Overseen By Kelly Huang

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Stanford University

Disqualifiers: Citrus allergy, Pregnant, Lactating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 9 weeks

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests d-limonene, a dietary supplement, to determine if it can safely reduce severe dry mouth in patients undergoing treatment for head and neck cancer. Participants will also receive standard cancer treatments, such as chemotherapy (specifically, Cisplatin) and radiation. The trial includes different groups receiving various doses of d-limonene to identify the optimal amount for alleviating dry mouth. Eligible participants have head and neck cancer and are scheduled to begin chemotherapy and radiation. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

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

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

A previous study showed that d-limonene has potential as a dietary supplement. Found in citrus peels, it is often used in food and cleaning products. Research indicates that while generally considered safe, it can cause skin irritation and allergic reactions, leading to redness or burning on the skin.

Swallowing d-limonene incorrectly poses a risk, potentially causing nausea, vomiting, or headaches. As this study is in an early stage, the main goal is to assess the safety of d-limonene when combined with cancer treatments like chemotherapy and radiation. These early stages help researchers understand any potential side effects or risks in this context.

Although d-limonene is already widely available and used, its safety in cancer treatment settings remains under study. Participants in the trial will provide valuable insights into its safety for this specific use. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for dry mouth in head and neck cancer patients focus on managing symptoms after they appear, often using saliva substitutes or stimulants. But d-limonene stands out because it's a natural compound found in citrus oils that might prevent dry mouth from developing in the first place. Unlike standard treatments, d-limonene could protect salivary glands during chemoradiation by acting as an anti-inflammatory and antioxidant agent. This preventative approach is what has researchers excited, as it could significantly improve the quality of life for patients undergoing cancer treatment.

What evidence suggests that this trial's treatments could be effective for preventing dry mouth in head and neck cancer patients?

Research shows that d-limonene, a substance in citrus oils, might help with dry mouth in cancer patients. Studies have found that d-limonene can increase saliva production, potentially reducing discomfort from radiation therapy. One study discovered that this natural citrus oil effectively relieved dry mouth when combined with certain fat-based formulations. Additionally, animal studies have shown that d-limonene protects saliva production. This trial will investigate various dosages of d-limonene to determine its effectiveness in preventing dry mouth during chemoradiation for head and neck cancer. These findings suggest that d-limonene could be a promising option for those experiencing dry mouth from cancer treatment. ^{6 7 8 9 10}

Who Is on the Research Team?

Quynh-Thu Le

Principal Investigator

Stanford Universiy

Are You a Good Fit for This Trial?

This trial is for adults with advanced head and neck squamous cell carcinoma, who are about to receive chemoradiation. They must be able to swallow pills, not have citrus allergies, and women must not be pregnant or breastfeeding. Participants need good liver, kidney, and blood function and a performance status indicating they can care for themselves.

Inclusion Criteria

I have a confirmed diagnosis of advanced throat cancer and am scheduled for chemoradiation.

I have squamous cell carcinoma in my head or neck with unknown origin, but it has spread to my nodes.

I am not pregnant and agree to use birth control during the d-limonene treatment.

Exclusion Criteria

Pregnant or lactating

History of allergic reactions attributed to citrus fruits

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive d-limonene in combination with radiation and platinum-based chemotherapy

9 weeks

Weekly visits for monitoring and administration

Adjuvant Treatment

Participants continue with adjuvant administration of d-limonene for compliance assessment

14 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Cisplatin
• D Limonene
• D-Limonene Gelcaps
• Intensity modulated radiotherapy (IMRT)
• Xerostomia questionnaire

Trial Overview

The study tests if d-Limonene gelcaps can prevent dry mouth in cancer patients undergoing radiation and platinum-based chemotherapy. It also involves completing questionnaires about xerostomia symptoms to assess the effectiveness of the treatment.

How Is the Trial Designed?

Group I: de-escalation dose d-limonene -6gram Experimental Treatment 4 Interventions

6 gram d-limonene orally, as 3 grams 2 times daily delivered during chemoradiation

Group II: de-escalation dose d-limonene -4gram Experimental Treatment 4 Interventions

4 gram d-limonene orally, as 2 grams 2 times daily delivered during chemoradiation

Group III: de-escalation dose d-limonene -2gram Experimental Treatment 4 Interventions

2 gram d-limonene orally, once daily delivered during chemoradiation

Group IV: d-limonene -8gram Experimental Treatment 4 Interventions

8 gram d-limonene orally, as 4 grams 2 times daily delivered during chemoradiation

Group V: d-limonene -6gram Experimental Treatment 4 Interventions

6 gram d-limonene orally, as 3 grams 2 times daily delivered during chemoradiation

Group VI: d-limonene -4gram Experimental Treatment 4 Interventions

4 gram d-limonene orally, as 2 grams 2 times daily delivered during chemoradiation

Group VII: d-limonene -2gram Experimental Treatment 4 Interventions

2 gram d-limonene orally, once daily delivered during chemoradiation

Cisplatin is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Quynh-Thu Le

Lead Sponsor

Trials

1

Recruited

20+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Published Research Related to This Trial

In a study of 83 head and neck cancer patients, a three-weekly chemotherapy schedule (cisplatin 100 mg/m2) resulted in less overall toxicity compared to a weekly schedule (cisplatin 40 mg/m2), particularly in terms of severe mucositis and treatment interruptions.

The weekly chemotherapy regimen was associated with higher rates of grade III skin and hematological toxicity, suggesting that while it may be effective, it poses greater risks of acute side effects compared to the three-weekly approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of acute toxicities of two chemotherapy schedules for head and neck cancers. Geeta, SN., Padmanabhan, TK., Samuel, J., et al.[2022]

In a pilot study involving three patients with advanced head and neck cancer, the combination of radiation therapy and cisplatin (CDDP) resulted in severe side effects, including abscesses and significant nausea and vomiting.

The observed toxicities were greater than expected from either treatment alone, raising concerns about the safety of using this combination in routine clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concomitant radiation therapy and cis-diamminedichloroplatinum (II) in patients with advanced head and neck cancer. Creagan, ET., Fountain, KS., Frytak, S., et al.[2019]

The addition of low-dose cisplatin (CDDP) to hyperfractionated radiation therapy (Hfx RT) significantly improved survival rates in patients with locally advanced squamous cell carcinoma of the head and neck, with 68% survival at 2 years compared to 49% with Hfx RT alone.

Despite the survival benefits, the combination treatment did not increase the incidence of severe radiation-induced toxicity compared to Hfx RT alone, although higher rates of hematologic toxicity were observed in patients receiving CDDP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. Jeremic, B., Shibamoto, Y., Milicic, B., et al.[2022]

In a study of 35 patients with advanced squamous cell carcinoma of the head and neck, the combination of cis-platinum (CDDP) and radiotherapy (RT) resulted in a high complete response rate of 75%, with an overall response rate of 100%.

The treatment was well tolerated, with gastrointestinal and hematologic toxicities being the most common side effects, making CDDP plus RT a safe and effective option, especially for patients with good performance status and unresectable stage II or III disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simultaneous cis-platinum and radiotherapy in inoperable or locally advanced squamous cell carcinoma of the head and neck. Gasparini, G., Pozza, F., Recher, G., et al.[2018]

In a study of 41 patients with advanced oral squamous cell carcinoma, a preoperative treatment combining cisplatin or carboplatin with irradiation resulted in a high overall response rate of 97.6%, with 61% achieving a complete response.

The treatment was well tolerated, with low and reversible side effects, and led to a promising 5-year survival rate of 81.5%, indicating its effectiveness even in advanced stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preoperative simultaneous cisplatin- or carboplatin-based chemotherapy and radiotherapy for squamous cell carcinoma of the oral cavity. Kirita, T., Ohgi, K., Tsuyuki, M., et al.[2013]

Cisplatin-based concurrent chemoradiation is a crucial treatment for patients with unresectable locally advanced squamous cell carcinoma of the head and neck, but the standard 3-weekly regimen of 100 mg/m2 is often linked to significant adverse events.

There is a need for large prospective randomized trials to compare the standard 3-weekly cisplatin regimen with a weekly schedule (30-40 mg/m2) to determine which is more tolerable and effective, particularly regarding side effects like mucositis and dermatitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Three Weekly Versus Weekly Cisplatin as Radiosensitizer in Head and Neck Cancer: a Decision Dilemma. Negi, P., Kingsley, PA., Srivastava, H., et al.[2019]

In a study involving 129 patients with locally advanced epithelial malignancies, high-dose cisplatin (100 mg/m2) combined with radiation showed promising median survival times, particularly for squamous cell carcinoma of the head and neck, which had a median survival of 36 months.

The treatment was administered every 3 weeks during radiation therapy, and while median survival times for ovarian and lung cancers were 19 and 14 months respectively, some cancers like cervical carcinoma and prostate adenocarcinoma have not yet reached median survival, indicating ongoing effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with high-dose cisplatin and radiation for treatment of epithelial malignancies. Coughlin, CT.[2013]

In a phase I study involving 12 patients with locoregionally advanced head and neck cancer, the combination of low-dose cisplatin and docetaxel with radiotherapy showed promising efficacy, with complete response rates ranging from 33% to 67% across different docetaxel dose levels.

The treatment was generally well-tolerated, with minimal hematological toxicities and no grade 4 toxicities, although grade 3 mucositis was common, indicating that while effective, careful monitoring of side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent chemoradiotherapy with cisplatin and docetaxel for advanced head and neck cancer. A phase I study. Inohara, H., Inoue, T., Akahani, S., et al.[2018]

In a study of 60 patients with locally advanced head and neck squamous cell carcinoma (HNSCC), weekly low-dose cisplatin (30 mg/m2) resulted in significantly lower acute toxicities compared to high-dose cisplatin (100 mg/m2 every 3 weeks), with 56.6% of patients experiencing severe side effects versus 76.6% in the high-dose group.

While the low-dose regimen had better patient compliance (70% completing at least 6 doses) and lower toxicity, it also resulted in a lower loco-regional control rate (57.6%) compared to the high-dose group (72.8%), indicating a trade-off between safety and treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin Weekly Versus Every 3 Weeks Concurrently with Radiotherapy in the Treatment of Locally Advanced Head and Neck Squamous Cell Carcinomas: What Is the Best Dosing and Schedule? Mashhour, K., Hashem, W.[2020]

Carboplatin-based chemoradiation therapy (CTRT) is a well-tolerated alternative for patients with locally advanced head and neck cancers who are unfit for cisplatin, with 84.1% of patients completing the planned treatment.

The study found a median overall survival of 28 months and progression-free survival of 17 months, suggesting that carboplatin-based CTRT may offer better outcomes compared to radical radiotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin-based concurrent chemoradiation therapy in locally advanced head and neck cancer patients who are unfit for cisplatin therapy. Noronha, V., Sharma, V., Joshi, A., et al.[2018]

The SMART technique for intensity modulated radiotherapy (IMRT) significantly reduces maximum and mean radiation doses to the skin and oral cavity in head and neck cancer patients, while maintaining acceptable coverage of the planning target volume (PTV).

In a study of 16 patients, the SMART technique reduced skin maximum doses from 64.2 Gy to 55.9 Gy and mean doses from 26.7 Gy to 20.2 Gy, indicating a potential for less treatment-related morbidity, particularly in skin toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Skin/mucosa avoidance radiotherapy (SMART) versus conventional volumetric arc-based radiotherapy (VMAT) for the treatment of head and neck cancer: Dosimetric feasibility study. Anderson, C., MacDonald, RL., Wilke, D.[2023]

In a study involving 22 patients with advanced head and neck cancer, a combination of high-dose cisplatin (CDDP) and prolonged infusion of 5-fluorouracil (5-FU) alongside radiation therapy was tested for safety and maximum tolerated dose.

The treatment regimen resulted in significant side effects, including severe mucositis and myelosuppression, but identified potential doses of 35 mg/m2/day for CDDP and 200 mg/m2/day for 5-FU for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of high-dose cisplatin, prolonged infusion 5-fluorouracil, and concomitant conventional fraction radiation therapy in patients with inoperable squamous cell carcinoma of the head and neck. Salter, MM., Wheeler, RH., Peters, GE., et al.[2019]

In a study of 82 advanced head and neck cancer patients undergoing concurrent chemoradiotherapy with high-dose cisplatin, 26% experienced renal impairment, highlighting the need for careful monitoring of kidney function during treatment.

Risk factors for cisplatin-induced renal impairment included the use of calcium channel blockers and lower hemoglobin levels, while the use of proton pump inhibitors was associated with a reduced risk, suggesting potential strategies to enhance patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of Risk Factors for High-dose Cisplatin-induced Renal Impairment in Head and Neck Cancer Patients. Koide, H., Noda, S., Okunuki, Y., et al.[2022]

In a study of 20 patients with inoperable stage III and IV oral or oropharyngeal cancers, the combination of carboplatin and radiation therapy resulted in a 60% complete remission rate, indicating significant efficacy in treating these advanced cancers.

The treatment was well tolerated, with only 2 patients experiencing severe side effects that required interruptions, suggesting that carboplatin can be safely integrated into chemoradiation regimens for head and neck cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simultaneous radiochemotherapy in the treatment of inoperable, locally advanced head and neck cancers. Awasthy, BS., Julka, PK., Rath, GK., et al.[2013]

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Hazard Statements. H226. Flammable liquid and vapour. H304. May be fatal if swallowed and enters airways. H315. Causes skin irritation. H317.

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