De-intensified Chemoradiotherapy for Oropharyngeal Cancer

(PROTEcT Trial)

Recruiting at 1 trial location

Overseen By Kelsey Meyer

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: AHS Cancer Control Alberta

Disqualifiers: Metastatic disease, Prior head and neck cancer, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

32 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a less intense version of chemoradiotherapy for individuals with p16-positive squamous cell carcinoma of the oropharynx. Researchers aim to determine if reducing the radiation dose and area can effectively treat the cancer while potentially causing fewer side effects. Individuals diagnosed with this type of cancer and eligible for curative treatment, regardless of smoking status, might be suitable candidates. As an unphased trial, this study provides patients the opportunity to contribute to innovative research that could lead to less invasive treatment options.

Do I need to stop my current medications for this trial?

The trial information does not specify whether you need to stop taking your current medications. Please consult with the trial coordinators or your doctor for guidance.

What prior data suggests that de-intensified chemoradiotherapy is safe for oropharyngeal cancer?

Research shows that a gentler form of chemoradiotherapy is generally well-tolerated by patients. Studies have found that reducing treatment intensity can still yield good results for people with HPV-related throat cancer. Although one study found that some gentler treatments were less effective than standard treatment in preventing cancer recurrence over two years, the gentler approach still showed promise in controlling the disease.

Another study examined patients who received lower doses of chemoradiotherapy after initial chemotherapy, aiming to balance effectiveness and side effects. So far, results suggest that side effects can be reduced without significantly compromising the treatment's benefits.

Overall, while some approaches require further testing, the treatment appears safe for many patients. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about de-intensified chemoradiotherapy for oropharyngeal cancer because it aims to maintain effectiveness while reducing the intensity of treatment. Unlike the standard approach, which often involves higher doses of radiation and chemotherapy, this treatment uses a lower radiation dose of 60 Gy targeted specifically at the primary tumor and involved lymph nodes. This approach is designed to minimize side effects and improve the quality of life for patients during and after treatment. By reducing the volume of elective nodal radiation, the treatment could potentially lessen the long-term impact on surrounding healthy tissues, which is a significant advancement in cancer care.

What evidence suggests that de-intensified chemoradiotherapy might be an effective treatment for oropharyngeal cancer?

Research has shown that using a lower dose of combined chemotherapy and radiation for throat cancer yields promising results. In this trial, participants will receive de-intensified chemoradiotherapy, which reduces the radiation dose to 60 Gy, along with weekly doses of the chemotherapy drug cisplatin. Studies have found that this approach leads to good outcomes, with many patients not experiencing cancer progression for 2 to 3 years. However, some studies found that this reduced treatment approach did not achieve the same high success rates as standard treatment. Despite this, researchers remain interested in exploring this approach because it might reduce side effects while still being effective. ^{2 4 6 7 8}

Who Is on the Research Team?

Harvey Quon, MD

Principal Investigator

Tom Baker Cancer Centre

Are You a Good Fit for This Trial?

Adults with p16+ squamous cell carcinoma of the oropharynx, eligible for curative treatment, can join this trial. They must have certain tumor and nodal stages (T1-T3, N1-N2), good organ function, and an ECOG performance status of 0-2. Smokers and non-smokers are welcome. Those with metastatic disease, prior head and neck cancer/radiation, or who are pregnant cannot participate.

Inclusion Criteria

Smokers and non-smokers are included

Provide informed consent

My cancer is confirmed to be squamous cell carcinoma.

Exclusion Criteria

My cancer has spread to nearby lymph nodes or into the submandibular gland.

I have had radiation therapy on my head or neck before.

I cannot attend all radiotherapy sessions or follow-up visits.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiotherapy

De-intensified radiotherapy to a dose of 60 Gy to the primary tumour and involved lymph nodes and 54 Gy to subclinical regions at risk in 30 fractions

6 weeks

Chemotherapy

Concurrent cisplatin or cetuximab administered as per standard of care

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• De-intensified chemoradiotherapy

Trial Overview The PROTEcT study is testing a de-intensified chemoradiotherapy approach for patients with p16+ oropharyngeal cancer. It's a single-arm prospective cohort study across multiple centers aiming to see if reducing radiation volume and dose is effective.

How Is the Trial Designed?

Group I: De-intensified chemoradiotherapy Experimental Treatment 1 Intervention

Radiotherapy to a dose of 60 Gy to the primary tumour and involved lymph nodes and 54 Gy to subclinical regions at risk in 30 fractions. Reduced volume of elective nodal radiation.

De-intensified chemoradiotherapy is already approved in United States, European Union, Canada for the following indications:

Approved in United States as De-intensified chemoradiotherapy for:

• p16+ oropharyngeal cancer
• HPV-associated oropharyngeal squamous cell carcinoma

Approved in European Union as De-intensified chemoradiotherapy for:

• p16+ oropharyngeal cancer
• HPV-associated oropharyngeal squamous cell carcinoma

Approved in Canada as De-intensified chemoradiotherapy for:

• p16+ oropharyngeal cancer
• HPV-associated oropharyngeal squamous cell carcinoma

Who Is Running the Clinical Trial?

AHS Cancer Control Alberta

Lead Sponsor

Trials

188

Recruited

26,900+

Tom Baker Cancer Centre

Collaborator

Trials

30

Recruited

8,900+

Cross Cancer Institute

Collaborator

Trials

62

Recruited

19,200+

Published Research Related to This Trial

HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) is recognized as a distinct type of cancer that may benefit from personalized treatment strategies, including less invasive and less toxic therapies.

Current research is focused on de-escalation treatment strategies that aim to reduce the toxicity of standard treatments while maintaining effective disease control, but more conclusive results from ongoing trials are needed to determine the best approaches and which patients will benefit most.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Present and Future of De-intensification Strategies in the Treatment of Oropharyngeal Carcinoma. De Virgilio, A., Costantino, A., Mercante, G., et al.[2021]

In a systematic review of 55 studies involving 38,929 patients with HPV+ oropharyngeal carcinoma, de-intensified treatment approaches were found to significantly reduce overall survival (OS) and progression-free survival (PFS) compared to standard treatments.

The analysis indicated that reduced intensity treatments also led to decreased locoregional and distant disease control, suggesting that de-escalation strategies may pose a risk of providing sub-optimal care for patients with HPV+ OPC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment de-escalation for HPV+ oropharyngeal cancer: A systematic review and meta-analysis. Petrelli, F., Luciani, A., Ghidini, A., et al.[2022]

A systematic review of 10 prospective studies on therapy de-escalation for HPV-associated oropharyngeal cancer (OPC) suggests that reduced-dose chemoradiotherapy, especially when combined with induction chemotherapy, can achieve high 2-year progression-free survival (PFS) rates of 89% and overall survival (OS) rates of 96%.

While de-escalation strategies show promising efficacy, they also present some acute toxicities, with grade 3+ dysphagia and mucositis occurring in 9-39% of patients, indicating a need for careful patient selection and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

De-intensification of therapy in human papillomavirus associated oropharyngeal cancer: A systematic review of prospective trials. Patel, RR., Ludmir, EB., Augustyn, A., et al.[2021]

In a study of 62 patients with HPV+ oropharyngeal squamous cell carcinoma, a response-based de-escalation of radiotherapy and chemoradiotherapy resulted in high 2-year progression-free survival rates of 95% for low-risk and 94% for high-risk patients, demonstrating efficacy while reducing treatment intensity.

The study showed significantly lower rates of severe side effects, such as grade 3+ mucositis and PEG-tube use, in patients receiving lower doses of treatment (RT50 and CRT45) compared to standard care (CRT75), indicating a safer approach to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

OPTIMA: a phase II dose and volume de-escalation trial for human papillomavirus-positive oropharyngeal cancer. Seiwert, TY., Foster, CC., Blair, EA., et al.[2023]

In a phase II clinical trial involving 114 patients with HPV-associated oropharyngeal cancer, a de-intensified treatment regimen of 60 Gy radiotherapy and low-dose cisplatin resulted in excellent 2-year outcomes: 95% local-regional control and 86% progression-free survival.

The study found that this treatment approach minimized the need for chemotherapy and surgery, with no severe late adverse events reported, indicating a safer and effective option for patients with minimal smoking history.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Trial of De-Intensified Chemoradiotherapy for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma. Chera, BS., Amdur, RJ., Green, R., et al.[2021]

Oropharyngeal cancers caused by HPV are more sensitive to chemotherapy and radiation, leading to better outcomes compared to HPV-negative cancers, which raises questions about the intensity of current treatment protocols.

Ongoing de-escalation trials suggest that less intensive treatment regimens could maintain efficacy while reducing toxicity for HPV-positive patients, but clinicians are advised to wait for clinical trial results before changing treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment de-intensification strategies for HPV-driven oropharyngeal cancer: A short review]. Lahmamssi, C., Guy, JB., Benchekroun, N., et al.[2020]

A systematic review of 13 studies showed that reducing the radiation dose for HPV-related oropharyngeal carcinoma (OPC) to less than 66 Gy resulted in better overall survival rates (95.66% at 2 years and 91.51% at 3 years) compared to the standard dose (88.36% at 2 years and 87.46% at 3 years).

Reducing the radiation dose significantly decreased treatment-related side effects, with oral mucositis being the most common complication (36.4%), thus improving the quality of life for patients while still maintaining effective cancer control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-dose radiation in human papillomavirus-associated oropharyngeal carcinoma can improve outcome: a systematic review and meta-analysis. Yang, MQ., Liu, YC., Sui, JD., et al.[2023]

In a phase 2 trial involving 45 patients with HPV-positive oropharyngeal cancer, de-escalated chemoradiation therapy resulted in a low rate of gastrostomy tube placement (5%) and allowed 95% of patients to return to a normal diet after treatment, indicating improved functional outcomes.

Patients who had a normal BMI before treatment were able to recover to baseline BMI levels approximately 18 months post-therapy, suggesting that the treatment approach may help maintain nutritional status and quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional Outcomes After De-escalated Chemoradiation Therapy for Human Papillomavirus-Positive Oropharyngeal Cancer: Secondary Analysis of a Phase 2 Trial. Hegde, JV., Shaverdian, N., Felix, C., et al.[2019]

In a phase 2 study involving 43 patients with favorable-risk HPV-associated oropharyngeal squamous cell carcinoma, a reduced intensity treatment of 60 Gy IMRT combined with low-dose cisplatinum resulted in a high pathologic complete response (pCR) rate of 86%.

The study also demonstrated a lower incidence of severe toxicities compared to standard treatments, with significant rates of mucositis and dysphagia, but overall, the treatment was well-tolerated, indicating a promising balance between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 Trial of De-intensified Chemoradiation Therapy for Favorable-Risk Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma. Chera, BS., Amdur, RJ., Tepper, J., et al.[2022]

HPV-related oropharyngeal cancers, which are becoming more common, show better treatment responses and overall survival compared to traditional tobacco-related cases, highlighting the importance of understanding their distinct biological behavior.

Current treatment strategies involve multi-disciplinary approaches, including chemoradiation and surgery, with ongoing research focused on reducing treatment toxicity and exploring novel immunotherapies for patients with recurrent or metastatic disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advanced oropharyngeal squamous cell carcinoma: Pathogenesis, treatment, and novel therapeutic approaches. Swiecicki, PL., Malloy, KM., Worden, FP.[2020]

Oropharyngeal carcinoma linked to human papillomavirus (HPV) is on the rise, but it has better treatment outcomes compared to traditional head and neck cancers, prompting a focus on treatment de-escalation strategies.

Current strategies for reducing treatment intensity include adjusting radiation doses, using selective nodal irradiation, and evaluating patient responses to induction chemotherapy, all aimed at minimizing side effects while preserving quality of life for younger, healthier patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regional Radiation Therapy for Oropharyngeal Cancer in the HPV Era. Tam, M., Hu, K.[2019]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.6044

Two-year clinical outcomes of de-intensified ... Background: We here-in report 2 year cancer control outcomes from a prospective phase II clinical trial evaluating de-intensified ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9406155/

Current Evidence of a Deintensification Strategy for ... This article reviews the most recent evidence on the deintensification of HPV-related oropharyngeal cancer.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0360301625004754

A Phase 1 Study of Deintensified Hypofractionated ... Published phase 2 results of reduced dose radiation therapy (RT) of 60 Gy with weekly cisplatin have shown excellent outcomes with 2- to 3-year progression-free ...

4. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT02945631

Quarterback 2b - Sequential Therapy With Reduced Dose ... The purpose of this study is to establish the efficacy and toxicity of low dose chemoradiotherapy after induction chemotherapy in patients with locally ...

5. astro.org astro.org/news-and-publications/news-and-media-center/news-releases/2024/astro24yom

Existing standard chemoradiation superior to ... Randomized trial halted after two deintensification strategies failed to match standard of care's 98% rate of two-year progression-free survival.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29243245/

Outcomes From the National Cancer Data Base Deintensification of treatment from chemoradiotherapy to radiotherapy or surgery alone in cases of HPV+ AJCC eighth edition stage I or stage II disease may ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0167814025002282

Associations between dosimetry and patient-reported ... In this study, we evaluated the relationship between PROs and doses to various OARs in oropharyngeal cancer patients from two elective neck irradiation (ENI) ...

8. healio.com healio.com/news/hematology-oncology/20190826/deintensified-chemoradiotherapy-confers-favorable-outcomes-in-hpvassociated-oropharyngeal-cancer

De-intensified chemoradiotherapy confers favorable ... A de-intensified chemoradiotherapy regimen conferred favorable clinical outcomes among patients with HPV-associated oropharyngeal squamous ...