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

Overseen by Quynh-Thu Le

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Stanford University

Disqualifiers: Citrus allergy, Pregnant, Lactating

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests the safety of d-limonene, a citrus supplement, for head and neck cancer patients with severe dry mouth. It aims to find the safe dose and see if it can help increase saliva production to ease dry mouth symptoms.

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.

What data supports the effectiveness of the treatment d-Limonene + Radiation + Chemo for preventing dry mouth in head and neck cancer?

Research shows that cisplatin-based chemotherapy combined with radiation therapy is effective in controlling tumors and improving survival in head and neck cancer. Additionally, intensity modulated radiotherapy (IMRT) helps reduce radiation doses to normal tissues, like salivary glands, which may help in preventing dry mouth. ^{1 2 3 4 5}

Is the combination of d-Limonene, radiation, and chemotherapy safe for preventing dry mouth in head and neck cancer patients?

The combination of cisplatin (a chemotherapy drug) and radiation has been studied in head and neck cancer patients, showing some common side effects like nausea, vomiting, and kidney issues. However, it is generally considered effective and safe when used with caution. There is no specific safety data available for d-Limonene in this combination, but cisplatin and radiation have been used together safely in other studies. ^{6 7 8 9 10}

How is the treatment with d-Limonene, radiation, and chemo different for preventing dry mouth in head and neck cancer?

This treatment is unique because it combines d-Limonene, a natural compound found in citrus oils, with radiation and chemotherapy to specifically target dry mouth prevention, which is a common side effect of head and neck cancer treatments. Traditional treatments focus on controlling the cancer itself, while this approach aims to improve quality of life by addressing a specific side effect. ^{1 11 12 13 14}

Research Team

Quynh-Thu Le

Principal Investigator

Stanford Universiy

Eligibility Criteria

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

Trial Timeline

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

Treatment Details

Interventions

• Cisplatin (Alkylating agents)
• D Limonene (Other)
• D-Limonene Gelcaps (Other)
• Intensity modulated radiotherapy (IMRT) (Radiation)
• Xerostomia questionnaire (Other)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Dr. Richard A. Miller

Stanford University

Chief Executive Officer since 2023

Stanford University, MD

Dr. Robert Schott

Stanford University

Chief Medical Officer since 2021

University of Michigan, MD

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Dr. Jeanne Marrazzo

National Institutes of Health (NIH)

Chief Medical Officer

MD from University of California, Los Angeles

Dr. Jay Bhattacharya

National Institutes of Health (NIH)

Chief Executive Officer

MD, PhD from Stanford University

Findings from Research

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]

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 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]

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 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 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]

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 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 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 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]

References

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

Preoperative simultaneous cisplatin- or carboplatin-based chemotherapy and radiotherapy for squamous cell carcinoma of the oral cavity. [2013]

2. Greece pubmed.ncbi.nlm.nih.gov

Concurrent chemoradiotherapy with cisplatin and docetaxel for advanced head and neck cancer. A phase I study. [2018]

3. Thailand 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? [2020]

4. India pubmed.ncbi.nlm.nih.gov

Carboplatin-based concurrent chemoradiation therapy in locally advanced head and neck cancer patients who are unfit for cisplatin therapy. [2018]

5. United States 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. [2023]

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

Concomitant radiation therapy and cis-diamminedichloroplatinum (II) in patients with advanced head and neck cancer. [2019]

7. Greece pubmed.ncbi.nlm.nih.gov

Analysis of Risk Factors for High-dose Cisplatin-induced Renal Impairment in Head and Neck Cancer Patients. [2022]

8. Thailand pubmed.ncbi.nlm.nih.gov

Three Weekly Versus Weekly Cisplatin as Radiosensitizer in Head and Neck Cancer: a Decision Dilemma. [2019]

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

Simultaneous cis-platinum and radiotherapy in inoperable or locally advanced squamous cell carcinoma of the head and neck. [2018]

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

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

11. United States 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. [2022]

12. India pubmed.ncbi.nlm.nih.gov

Comparison of acute toxicities of two chemotherapy schedules for head and neck cancers. [2022]

13. United States 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. [2019]

14. India pubmed.ncbi.nlm.nih.gov

Simultaneous radiochemotherapy in the treatment of inoperable, locally advanced head and neck cancers. [2013]