Surgery + Reduced-Dose Radiation Therapy for Oropharyngeal Cancer

Overseen By Samantha Demko, RN, BSN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Heath Skinner

Disqualifiers: Pregnancy, Breast-feeding, Uncontrolled diabetes, others

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 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

150 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a trial studying patients with human papilloma virus (HPV) positive oropharyngeal cancer with tumors that can be removed via transoral surgery. Following surgery, patients will be classified as either low, intermediate, or high risk based on the characteristics of the tumors. Low risk patients (Arm S) will receive no further treatment after surgery. Intermediate risk patients (Arm RT) will be treated with Intensity Modulated Radiotherapy (IMRT) after surgery. High risk patients (Arm CRT) will receive a combination of IMRT and chemotherapy after surgery. Patients will be followed for up to five years after the completion of treatment.

Do I have to stop taking my current medications for the trial?

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 this treatment for oropharyngeal cancer?

Research suggests that minimally invasive transoral surgery can provide similar cancer control with better functional outcomes compared to chemoradiotherapy for oropharyngeal cancer. Additionally, reduced-dose radiotherapy may offer comparable survival rates with potentially fewer side effects for HPV-positive oropharyngeal cancer. ^{1 2 3 4 5}

Is the combination of surgery and reduced-dose radiation therapy safe for treating oropharyngeal cancer?

Research indicates that transoral robotic surgery (a type of surgery done through the mouth) is generally safe compared to traditional open surgery for oropharyngeal cancer. Additionally, reducing the dose of radiation therapy after surgery may help lower long-term side effects, improving quality of life. ^{6 7 8 9 10}

How is the treatment of surgery plus reduced-dose radiation therapy for oropharyngeal cancer different from other treatments?

This treatment is unique because it combines surgery with a lower dose of radiation therapy, which may reduce side effects compared to traditional high-dose radiation. It focuses on removing the cancer surgically and then using less intense radiation to minimize damage to surrounding healthy tissues. ^{2 11 12 13 14}

Research Team

Heath D. Skinner

Principal Investigator

UPMC Hillman Cancer Center

Eligibility Criteria

This trial is for adults with HPV-positive oropharyngeal cancer that can be surgically removed. Participants must have no prior radiation above the clavicles, a specific tumor stage (III, IVa, or IVb without distant metastases), and good heart, kidney, and liver function. They should not have had another cancer in the last two years (with some exceptions) and must be generally fit (ECOG 0-1). Pregnant women and individuals with uncontrolled diabetes or hypertension are excluded.

Inclusion Criteria

I am eligible for a TOS procedure and have no signs of cancer spread in my body.

My throat cancer is HPV-related, confirmed by a specific protein test.

I have had serious heart or stroke issues in the last 6 months.

Exclusion Criteria

I don't have any health issues that could affect my treatment or surgery.

Women must not be pregnant or breast-feeding due to the teratogenicity of chemotherapy

I don't have uncontrolled diabetes, infections despite antibiotics, or high blood pressure in the last 30 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgery

Participants undergo transoral surgical resection of the oropharyngeal tumor

1 week

1 visit (in-person)

Adjuvant Treatment

Intermediate risk patients receive low-dose IMRT for 3 weeks; high risk patients receive IMRT and weekly chemotherapy for 5 weeks

3-5 weeks

5-6 visits per week (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Treatment Details

Interventions

• Carboplatin
• Cisplatin
• Intensity-Modulated Radiation Therapy
• Therapeutic Conventional Surgery

Trial Overview The study tests transoral surgery followed by different treatments based on risk level: low-risk patients get no further treatment; intermediate-risk receive Intensity Modulated Radiotherapy (IMRT); high-risk get IMRT plus chemotherapy. The aim is to see if less aggressive therapy after surgery works well for certain risk groups.

Participant Groups

Group I: Arm S (Low Risk) Experimental Treatment 3 Interventions

Low risk patients are defined as T1-T2 AND 0 or 1 metastatic lymph nodes AND \<3 cm AND clear (≥3mm) margins AND no extracapsular extension (ECE) AND no perineural invasion AND no lymphovascular invasion. Patients will undergo transoral surgical resection of the oropharyngeal tumor.

Group II: Arm RT (Intermediate Risk) Experimental Treatment 4 Interventions

Intermediate risk patients are defined as having any of the following features: One or more close (\<3mm) margins, OR "minimal" ≤1 mm ECE OR 1 or more metastatic lymph nodes \>3 cm in diameter OR 2-4 lymph nodes positive (≤ 6 cm in diameter), OR perineural invasion OR lymphovascular invasion Patients will undergo transoral surgical resection of the oropharyngeal tumor. Following surgery, patients will receive low-dose IMRT five times a week for 3 weeks.

Group III: Arm CRT (High Risk) Experimental Treatment 6 Interventions

High risk patients are defined as having any of the following features: One or more positive margins OR \>1 mm ECE OR ≥ 5 metastatic lymph nodes. Patients will undergo transoral surgical resection of the oropharyngeal tumor. Following surgery, patients will receive low-dose IMRT six times a week and a weekly chemotherapy infusion (cisplatin or carboplatin) during radiation therapy. Patients will receive 2 Gy/fraction, 6 fractions per week with at least a 6-hour interfraction interval between each treatment: * PTV-P50 or PTV-N50: 50 Gy in 25 fractions (2 Gy/fx) * PTV-N45: 45 Gy in 25 fractions (1.8 Gy/fx) with simultaneous integrated boost to the PTV-P50 volume. * PTV-P30 or PTV-N30: 30 Gy in 15 fractions (2 Gy/fx)

Therapeutic Conventional Surgery is already approved in United States, European Union for the following indications:

Approved in United States as Therapeutic Conventional Surgery for:

• Resectable p16+ Locally Advanced Oropharynx Cancer

Approved in European Union as Transoral Surgical Resection for:

• HPV-positive oropharyngeal cancer

Who Is Running the Clinical Trial?

Heath Skinner

Lead Sponsor

Trials

4

Recruited

330+

Findings from Research

In a study of 17 patients with advanced oropharyngeal cancer, treatment with neoadjuvant chemotherapy followed by transoral surgery (TOS) resulted in a high disease-specific survival rate of 94.1% at 3 years, with 16 out of 17 patients alive without recurrence after a median follow-up of 31 months.

This approach demonstrates that combining chemotherapy with TOS and neck dissection is a feasible and effective strategy for managing moderately advanced oropharyngeal cancer, potentially allowing for the postponement of radiotherapy for cases with adverse features.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemotherapy and transoral surgery as a definitive treatment for oropharyngeal cancer: A feasible novel approach. Sadeghi, N., Li, NW., Taheri, MR., et al.[2018]

Transoral Robotic Surgery (TORS) for Stage III-IV HPV negative oropharyngeal cancer showed promising long-term results, with 81.7% of patients remaining disease-free and an overall survival rate of 91.5% after an average follow-up of 48 months.

The study suggests that TORS can effectively intensify treatment while minimizing the toxic effects associated with higher doses of traditional radiotherapy or chemoradiotherapy, leading to improved oncological outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oncological outcome following initiation of treatment for stage III and IV HPV negative oropharyngeal cancers with transoral robotic surgery (TORS). Dabas, S., Gupta, K., Sharma, AK., et al.[2020]

Transoral laser microsurgery (TLM) for oropharyngeal squamous cell carcinoma (OPSCC) showed promising results, with a 92% locoregional control rate and 81% disease-specific survival over a mean follow-up of 27 months in a cohort of 26 patients.

TLM resulted in minimal complications, with no patients becoming gastrostomy dependent, suggesting it is a safe and effective alternative to chemoradiotherapy for selected OPSCC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of transoral laser microsurgery for oropharyngeal squamous cell carcinoma in Ireland and review of the literature on transoral approaches. Woods, RSR., Geyer, L., Ionescu, A., et al.[2020]

This review aims to compare overall survival rates between standard and reduced-dose radiotherapy in patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC), potentially allowing for less toxic treatment options.

The study will include adult patients who have received curative treatment for HPV+ OPSCC, and it will systematically analyze existing literature to determine if lower radiation doses can maintain similar survival outcomes while reducing side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of reduced- versus standard-dose radiotherapy on survival and radiation-associated toxicity in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma: a systematic review protocol. Lee, TJ., Krishnan, G., Ooi, EH., et al.[2022]

In a study of 2635 patients with HPV-negative oropharyngeal squamous cell carcinoma, primary surgery significantly improved 5-year overall survival compared to radiation therapy in early-stage cancers (T1-2 N0-1), with survival rates of 76.2% versus 56.8%.

For more advanced stages (T3-4 N0-1 and T1-2 N2-3), surgery with adjuvant treatment also showed better survival outcomes compared to chemoradiation therapy, indicating that primary surgery may be a more effective treatment option for many patients with HPV-negative OPSCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human Papillomavirus-Negative Oropharyngeal Cancer Survival Outcomes Based on Primary Treatment: National Cancer Database Analysis. Shama, M., Al-Qurayshi, Z., Dahl, M., et al.[2022]

In a study involving 68 patients with oropharyngeal squamous cell carcinoma, those treated with radiotherapy reported better swallowing-related quality of life scores one year after treatment compared to those who underwent transoral robotic surgery (TORS) with neck dissection, although the difference was not clinically significant.

The study also found that radiotherapy was associated with higher rates of neutropenia, hearing loss, and tinnitus, while TORS patients experienced more cases of trismus, highlighting different toxicity profiles between the two treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy versus transoral robotic surgery and neck dissection for oropharyngeal squamous cell carcinoma (ORATOR): an open-label, phase 2, randomised trial. Nichols, AC., Theurer, J., Prisman, E., et al.[2020]

In a study of 726 patients with oropharyngeal squamous cell carcinoma, those who underwent primary transoral robotic surgery (TORS) experienced a higher risk of short-term dysphagia compared to those receiving radiation therapy or chemoradiation therapy (RT/CRT).

Patients treated with RT/CRT had worse 5-year overall survival rates (58.4%) compared to those who underwent primary TORS (70.2%), indicating that TORS may offer better long-term survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differences in Functional and Survival Outcomes Between Patients Receiving Primary Surgery vs Chemoradiation Therapy for Treatment of T1-T2 Oropharyngeal Squamous Cell Carcinoma. Amin, DR., Philips, R., Bertoni, DG., et al.[2023]

Transoral robotic surgery (TORS) for oropharyngeal cancer showed a significantly higher disease-free survival rate compared to conventional open surgery, based on a systematic review of 9 studies involving 574 patients.

TORS was associated with lower risks of complications, such as the need for free flap reconstruction, and resulted in a shorter hospital stay and quicker recovery times, although further long-term studies are needed to confirm these benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative safety and effectiveness of transoral robotic surgery versus open surgery for oropharyngeal cancer: A systematic review and meta-analysis. Park, DA., Lee, MJ., Kim, SH., et al.[2022]

A de-escalation strategy of reduced adjuvant radiation and chemotherapy after surgery for HPV-positive oropharyngeal cancer resulted in low long-term toxic effects, with only 1.4% experiencing grade 2 toxic effects at 1 year and no grade 4-5 toxic effects reported.

Patients showed significant improvements in swallow function and quality of life over time, with most returning to baseline levels, indicating that this treatment approach is both effective and preserves patient well-being.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Toxic Effects, Swallow Function, and Quality of Life on MC1273: A Phase 2 Study of Dose De-escalation for Adjuvant Chemoradiation in Human Papillomavirus-Positive Oropharyngeal Cancer. Price, K., Van Abel, KM., Moore, EJ., et al.[2022]

Transoral robotic surgery (TORS) for HPV-negative oropharyngeal squamous cell carcinoma (OPSCC) showed promising oncologic outcomes, with a 3-year overall survival rate of 85.5% and disease-free survival rate of 73.6% among 56 patients studied.

The TORS approach resulted in low perioperative morbidity, with only 1.8% experiencing mortality and a 5.4% rate of long-term gastrostomy, indicating it is a safer surgical option compared to traditional methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oncologic outcomes of transoral robotic surgery for HPV-negative oropharyngeal carcinomas. Parhar, HS., Weinstein, GS., O'Malley, BW., et al.[2021]

Surgery is becoming increasingly important in the treatment of oropharyngeal squamous cell cancer, especially when there is significant local infiltration or regional metastases, as it can enhance the chances of a cure compared to traditional radiation-based therapies.

In cases where chemoradiation has failed, primary surgery followed by postoperative radiotherapy may be considered, particularly with advanced techniques that reduce morbidity, making it a valuable alternative to chemoradiation in selected patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Surgical treatment options in oropharyngeal cancer]. Swoboda, H.[2022]

In a study of 71 patients with stage III and IV oropharyngeal carcinoma treated with intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy, the 3-year overall survival rate was 83%, indicating effective treatment outcomes.

IMRT allowed for excellent local and regional control of the cancer with minimal severe late effects, as only one patient experienced significant late toxicity, highlighting the safety and efficacy of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intensity-modulated chemoradiation for treatment of stage III and IV oropharyngeal carcinoma: the University of California-San Francisco experience. Huang, K., Xia, P., Chuang, C., et al.[2019]

In a study of 51 patients with locally advanced oropharyngeal carcinoma treated with surgery and postoperative radiotherapy, the 3-year overall survival rate was 51%, with local-regional control at 73% and freedom from distant metastases at 69%.

The number of pathologically positive lymph nodes was a significant predictor of treatment failure, highlighting the need for improved strategies to address distant metastases and functional outcomes after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advanced oropharyngeal carcinoma treated with surgery and radiotherapy: oncologic outcome and functional assessment. Denittis, AS., Machtay, M., Rosenthal, DI., et al.[2007]

Patients with stage IV and stage T3 N0-1 oropharyngeal squamous cell carcinoma (OPSCC) should receive concurrent high-dose intermittent cisplatin during definitive radiation therapy (RT) to enhance treatment efficacy.

Adjuvant RT after surgery for OPSCC with positive margins or extracapsular extension should also include concurrent high-dose intermittent cisplatin, but those intolerant to cisplatin should not routinely receive systemic therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation therapy for oropharyngeal squamous cell carcinoma: Executive summary of an ASTRO Evidence-Based Clinical Practice Guideline. Sher, DJ., Adelstein, DJ., Bajaj, GK., et al.[2018]

References

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

Neoadjuvant chemotherapy and transoral surgery as a definitive treatment for oropharyngeal cancer: A feasible novel approach. [2018]

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

Oncological outcome following initiation of treatment for stage III and IV HPV negative oropharyngeal cancers with transoral robotic surgery (TORS). [2020]

3. Ireland pubmed.ncbi.nlm.nih.gov

Outcomes of transoral laser microsurgery for oropharyngeal squamous cell carcinoma in Ireland and review of the literature on transoral approaches. [2020]

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

Effectiveness of reduced- versus standard-dose radiotherapy on survival and radiation-associated toxicity in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma: a systematic review protocol. [2022]

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

Human Papillomavirus-Negative Oropharyngeal Cancer Survival Outcomes Based on Primary Treatment: National Cancer Database Analysis. [2022]

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

Radiotherapy versus transoral robotic surgery and neck dissection for oropharyngeal squamous cell carcinoma (ORATOR): an open-label, phase 2, randomised trial. [2020]

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

Differences in Functional and Survival Outcomes Between Patients Receiving Primary Surgery vs Chemoradiation Therapy for Treatment of T1-T2 Oropharyngeal Squamous Cell Carcinoma. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Comparative safety and effectiveness of transoral robotic surgery versus open surgery for oropharyngeal cancer: A systematic review and meta-analysis. [2022]

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

Long-Term Toxic Effects, Swallow Function, and Quality of Life on MC1273: A Phase 2 Study of Dose De-escalation for Adjuvant Chemoradiation in Human Papillomavirus-Positive Oropharyngeal Cancer. [2022]

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

Oncologic outcomes of transoral robotic surgery for HPV-negative oropharyngeal carcinomas. [2021]

11. Austria pubmed.ncbi.nlm.nih.gov

[Surgical treatment options in oropharyngeal cancer]. [2022]

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

Intensity-modulated chemoradiation for treatment of stage III and IV oropharyngeal carcinoma: the University of California-San Francisco experience. [2019]

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

Advanced oropharyngeal carcinoma treated with surgery and radiotherapy: oncologic outcome and functional assessment. [2007]

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

Radiation therapy for oropharyngeal squamous cell carcinoma: Executive summary of an ASTRO Evidence-Based Clinical Practice Guideline. [2018]