Personalized De-escalation Treatment for Oropharyngeal Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Michigan Rogel Cancer Center

Must not be taking: Paclitaxel, Carboplatin

Disqualifiers: Prior invasive malignancy, Severe co-morbidity, Pregnancy, 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

Compensation: Varies

Number of Visits: Unknown

150 Participants Needed

Trial Summary

What is the purpose of this trial?

Single center, non-randomized Phase II study enrolling Stage I-II p16+ oropharyngeal cancer patients to one of two de-escalation treatment paradigms: (1) receive surgery followed by observation or risk-adjusted adjuvant radiation (+/-chemo), or (2) individualized adaptive definitive chemoradiation (CRT).

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you have poorly controlled diabetes, adjustments to your medications might be necessary. It's best to discuss your specific situation with the trial team.

What data supports the effectiveness of this treatment for oropharyngeal cancer?

Research shows that de-escalation treatment protocols, which involve reducing the intensity of treatment, can improve survival rates for patients with HPV-positive oropharyngeal cancer when using platinum-based chemotherapy combined with radiotherapy. This approach is supported by a meta-analysis indicating better overall survival and disease-specific survival for these patients. ^{1 2 3 4 5}

Is the personalized de-escalation treatment for oropharyngeal cancer safe?

Research on treatments like chemoradiation and adjuvant radiotherapy for oropharyngeal cancer shows that they can have side effects, but these are being studied to improve safety. A new system is being developed to better understand and manage these side effects, which helps doctors and patients make informed decisions. ^{2 4 6 7 8}

How is the treatment 'Personalized De-escalation Treatment for Oropharyngeal Cancer' different from other treatments?

This treatment is unique because it focuses on de-escalating (reducing the intensity of) therapy for HPV-positive oropharyngeal cancer, aiming to maintain effectiveness while minimizing side effects. It involves a personalized approach using chemoradiation and surgery, which is different from the standard high-intensity treatments that often have more severe side effects. ^{7 9 10 11 12}

Research Team

Michelle Mierzwa, M.D.

Principal Investigator

University of Michigan Rogel Cancer Center

Eligibility Criteria

This trial is for adults over 18 with early-stage p16+ or HPV-positive squamous cell carcinoma of the oropharynx, who haven't had prior treatment for this cancer. They must have good bone marrow function and organ performance, no distant metastases, and be able to undergo PET/CT scans. Women and men must use birth control during the study.

Inclusion Criteria

My kidney function, measured by creatinine levels, is normal or nearly normal.

I am 18 years old or older.

History/physical examination, including documentation of weight within 4 weeks prior to registration

Exclusion Criteria

Active enrollment on another clinical trial involving active treatment for the study cancer

Severe, active co-morbidity

I have received treatment for my cancer before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgery and Observation/Risk-adjusted Adjuvant Treatment

Participants undergo surgery followed by observation or risk-adjusted adjuvant radiation (+/- chemo)

6-8 weeks

Definitive Chemoradiation (CRT)

Participants receive individualized adaptive definitive chemoradiation

6-8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• Chemoradiation
• Observation
• Post-operative radiation
• Surgery

Trial Overview The CuSToMIze trial at University of Michigan tests two less intense treatments for Stage I-II p16+ oropharyngeal cancer: (1) surgery followed by observation or adjusted radiation (+/- chemo), (2) personalized adaptive chemoradiation based on individual response.

Participant Groups

Group I: Definitive CRT Experimental Treatment 1 Intervention

Risk-adjusted definitive chemoradiation.

Group II: Surgery Active Control 4 Interventions

Surgery followed by risk-adjusted adjuvant treatment (observation, radiation, or chemoradiation).

Chemoradiation is already approved in China for the following indications:

Approved in China as Baizean for:

• Classical Hodgkin’s lymphoma (cHL)
• Locally advanced or metastatic urothelial carcinoma (UC)
• Locally advanced or metastatic non-small cell lung cancer (NSCLC)
• Advanced unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors
• Locally advanced or metastatic esophageal squamous cell carcinoma (ESCC)
• Recurrent or metastatic nasopharyngeal cancer (NPC)

Who Is Running the Clinical Trial?

University of Michigan Rogel Cancer Center

Lead Sponsor

Trials

303

Recruited

20,700+

Findings from Research

HPV-positive oropharyngeal cancer patients generally have a better prognosis and lower mortality rates compared to HPV-negative patients, leading to a reconsideration of treatment approaches.

Recent trials have explored de-intensification strategies for treating HPV-positive oropharyngeal cancer, aiming to reduce the side effects of standard chemo-radiotherapy without compromising treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

De-intensification for HPV positive oropharyngeal cancer: and yet it moves!: 2019 in review. Bonomo, P., Livi, L.[2020]

In a study comparing 26 patients receiving radiotherapy with cetuximab (cet-RT) to 27 patients receiving chemotherapy (chemo-RT) for HPV+ oropharyngeal cancer, both groups showed similar functional outcomes and quality of life over time, despite some initial worsening in swallowing and quality of life scores.

The results suggest that using cetuximab instead of chemotherapy for treatment de-intensification in HPV+ oropharyngeal cancer may not provide significant advantages, as both treatment approaches yielded excellent clinical outcomes without notable differences in patient functions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparisons of dysphagia and quality of life (QOL) in comparable patients with HPV-positive oropharyngeal cancer receiving chemo-irradiation or cetuximab-irradiation. Samuels, SE., Tao, Y., Lyden, T., et al.[2018]

In a study of 233 patients with advanced oropharyngeal squamous cell carcinoma, there was no significant difference in recurrence-free survival rates between those treated with primary surgery and those treated with radiotherapy, with rates of 76.3% and 84.9% at five years, respectively.

The primary pattern of failure for both treatment groups was distant metastatic disease, suggesting that while local failures occurred, they may be preventable through improved targeting in treatment planning, particularly near critical areas like the base of the skull.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival Outcomes and Patterns of Recurrence in Patients with Stage III or IV Oropharyngeal Cancer Treated with Primary Surgery or Radiotherapy. Debenham, BJ., Banerjee, R., Warkentin, H., et al.[2020]

In a study of 96 patients with locally advanced HPV-positive oropharyngeal cancer, both transoral robotic surgery (TORS) and intensity-modulated radiotherapy (IMRT) showed excellent survival rates, with overall survival at 97% for TORS and 98% for IMRT.

There were no significant differences in survival outcomes or treatment-related toxicities between the two treatment groups, suggesting that both approaches are effective and safe, but there is a need to refine treatments to minimize side effects while maintaining effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Upfront transoral robotic surgery (TORS) versus intensity-modulated radiation therapy (IMRT) in HPV-positive oropharyngeal cancer: real-world data from a tertiary comprehensive cancer centre. Zorzi, SF., Agostini, G., Chu, F., et al.[2022]

Patients with HPV+ oropharyngeal squamous cell carcinoma show significantly improved overall survival and disease-specific survival when treated with platinum-based chemotherapy combined with radiotherapy, as indicated by a meta-analysis of 1130 patients from nine ongoing randomized controlled trials.

One trial suggests that using the EGFR inhibitor cetuximab may lead to reduced survival outcomes in HPV+ patients, highlighting the need for careful consideration of treatment protocols in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma: a systematic review and meta-analysis of current clinical trials. Masterson, L., Moualed, D., Liu, ZW., et al.[2023]

Adjuvant intensity-modulated radiotherapy (IMRT) with or without chemotherapy (AT) significantly improved disease-free survival and local-regional control in HPV-positive oropharyngeal squamous cell carcinoma patients compared to definitive surgical therapy (ST), particularly in patients with tumors exhibiting extracapsular extension.

However, the AT approach was associated with higher toxicity rates, including dysphagia and mandibular osteonecrosis, with 19.0% of AT patients experiencing these issues compared to only 2.4% in the ST group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Magnitude of benefit for adjuvant radiotherapy following minimally invasive surgery in intermediate to high risk HPV-positive oropharyngeal squamous cell carcinoma. Pasalic, D., Funk, RK., García, JJ., et al.[2019]

In a study of 899 oropharyngeal cancer patients, those with HPV-positive tumors showed significantly better local and regional control rates compared to HPV-negative patients, indicating that HPV status is a crucial factor in treatment outcomes.

HPV-positive patients classified as low-risk (T1-3N0-2c) have a low risk of distant metastasis, but those with N2c status may not benefit from treatment deintensification strategies that exclude chemotherapy, as they showed lower distant control rates when treated with radiotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. O'Sullivan, B., Huang, SH., Siu, LL., et al.[2022]

A new tool was developed to standardize how treatment toxicity from chemoradiation therapy for oropharyngeal carcinoma is represented, helping doctors and patients make informed decisions about treatment options.

In a survey of 105 oncologists, mucositis and nausea were identified as the most distressing short-term toxicities, while pain and xerostomia were noted as the most concerning long-term effects, highlighting the importance of both short-term and long-term outcomes in treatment discussions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of a chemoradiation therapy toxicity staging system for oropharyngeal carcinoma. Goepfert, RP., Yom, SS., Ryan, WR., et al.[2015]

Recent randomized trials indicate that omitting or substituting cisplatin in the treatment of HPV-positive oropharyngeal cancer leads to worse survival outcomes, highlighting the risks of treatment de-escalation.

The Head and Neck Cancer International Group recommends that any de-escalation strategies should first be tested in phase II studies before moving to larger phase III trials, emphasizing the need for high-level evidence to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

De-Escalation After DE-ESCALATE and RTOG 1016: A Head and Neck Cancer InterGroup Framework for Future De-Escalation Studies. Mehanna, H., Rischin, D., Wong, SJ., et al.[2021]

HPV-related oropharyngeal cancers are on the rise in Western countries, prompting a need for tailored management strategies due to their unique cancer development and better prognosis compared to other cancers.

Recent clinical trials are exploring therapeutic de-escalation for these patients, suggesting that less aggressive treatment may be effective given their distinct oncogenesis and favorable outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Challenges and limits of therapeutic de-escalation for papillomavirus-related oropharyngeal cancer]. Modesto, A., Graff Cailleaud, P., Blanchard, P., et al.[2022]

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]

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]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

De-intensification for HPV positive oropharyngeal cancer: and yet it moves!: 2019 in review. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Comparisons of dysphagia and quality of life (QOL) in comparable patients with HPV-positive oropharyngeal cancer receiving chemo-irradiation or cetuximab-irradiation. [2018]

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

Survival Outcomes and Patterns of Recurrence in Patients with Stage III or IV Oropharyngeal Cancer Treated with Primary Surgery or Radiotherapy. [2020]

4. Italy pubmed.ncbi.nlm.nih.gov

Upfront transoral robotic surgery (TORS) versus intensity-modulated radiation therapy (IMRT) in HPV-positive oropharyngeal cancer: real-world data from a tertiary comprehensive cancer centre. [2022]

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

De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma: a systematic review and meta-analysis of current clinical trials. [2023]

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

Magnitude of benefit for adjuvant radiotherapy following minimally invasive surgery in intermediate to high risk HPV-positive oropharyngeal squamous cell carcinoma. [2019]

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

Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. [2022]

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

Development of a chemoradiation therapy toxicity staging system for oropharyngeal carcinoma. [2015]

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

De-Escalation After DE-ESCALATE and RTOG 1016: A Head and Neck Cancer InterGroup Framework for Future De-Escalation Studies. [2021]

10. France pubmed.ncbi.nlm.nih.gov

[Challenges and limits of therapeutic de-escalation for papillomavirus-related oropharyngeal cancer]. [2022]

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

Phase II Trial of De-Intensified Chemoradiotherapy for Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma. [2021]

12. England pubmed.ncbi.nlm.nih.gov

De-intensification of therapy in human papillomavirus associated oropharyngeal cancer: A systematic review of prospective trials. [2021]