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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new methods to treat oropharyngeal cancer linked to HPV. After conventional therapeutic surgery, patients will join one of three groups based on their cancer risk level. Low-risk patients will receive no further treatment, intermediate-risk patients will undergo reduced-dose radiation therapy, and high-risk patients will receive both radiation and chemotherapy. Individuals diagnosed with HPV-positive oropharyngeal cancer that can be surgically removed might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

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

A previous study demonstrated that a type of surgery performed through the mouth showed promising safety for patients with throat cancer. This surgery had low recurrence rates and was generally well-tolerated. Research indicates that patients experienced fewer complications compared to more invasive surgeries.

Studies have shown that Intensity-Modulated Radiation Therapy (IMRT) is also generally safe, causing fewer immediate side effects than some other treatments. Patients reported good results with a low risk of serious side effects.

For high-risk patients, chemotherapy is added. Cisplatin, a common chemotherapy drug, can cause side effects like nausea and mouth sores, but these are usually manageable. Carboplatin is another option with similar and well-known safety.

This trial is in Phase 2, indicating that the treatments have passed initial safety checks. These treatments have been well-studied and are generally considered safe for patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment approach because it explores the use of surgery combined with reduced-dose radiation therapy tailored to different risk groups for oropharyngeal cancer, aiming to maintain effectiveness while minimizing side effects. Unlike standard treatments that often involve full-dose radiation and chemotherapy for all patients, this method adjusts the intensity of therapy based on the patient's risk level. For low-risk patients, only surgery is performed, potentially reducing radiation-related side effects. Intermediate-risk patients receive a lower dose of radiation post-surgery, and high-risk patients are given a combination of reduced-dose radiation and chemotherapy, which could offer a more balanced treatment approach. This personalized strategy could improve quality of life by reducing unnecessary treatment intensity.

What evidence suggests that this trial's treatments could be effective for oropharyngeal cancer?

Research shows that surgery through the mouth, which participants in this trial will undergo, effectively treats HPV-positive throat cancer. Studies indicate that 92.4% of patients survive at least three years after this surgery. In this trial, intermediate-risk patients will receive Intensity Modulated Radiotherapy (IMRT) after surgery, which offers similar survival rates and helps prevent cancer recurrence. For high-risk patients, adding chemotherapy drugs like cisplatin or carboplatin to IMRT improves outcomes. These treatments are well-established for various cancers, including those in the head and neck, and have been proven to improve survival rates. ^{1 2 3 6 7}

Who Is on the Research Team?

Heath D. Skinner

Principal Investigator

UPMC Hillman Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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]

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 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]

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]

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]

Citations

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Survival outcomes in patients with oropharyngeal cancer ... Phase II trials have demonstrated 2-year overall survival of 66.6 % for stage III/IV resectable oro/hypopharyngeal treated with cisplatin, ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/27724969/

Survival Outcomes in Patients With Oropharyngeal Cancer ... Overall survival for all patients was 81.7 and 70.7 % at 3 and 5 years, respectively. Disease free survival and locoregional recurrence-free survival at 5 years ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0923753419412039

Long-term outcomes with concurrent carboplatin, paclitaxel ... Forty of 50 assessable patients (80%) had an objective response, with a complete response rate of 52%. With a median follow-up of 69 months for surviving ...

4. redjournal.org redjournal.org/article/S0360-3016(17)34269-4/fulltext

Outcomes Between Concurrent Cisplatin Versus ... Older age, region, and year of treatment predicted the use of carboplatin. There was no statistically significant difference in OS between ...

5. cancer.gov cancer.gov/types/head-and-neck/hp/adult/oropharyngeal-treatment-pdq

Oropharyngeal Cancer Treatment (PDQ®) - NCI The 5-year survival rate was 49% for surgery with or without radiation therapy versus 52% (P = .2) for radiation therapy with or without neck ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.6085

10-year outcomes of technically unresectable oral cancers ... The median OS was 9 months (95% CI: 8.6 – 9.4). NACT with more than 2-drugs had an OS of 13.2 months (95% CI: 12 – 14.4) vs 7.5 months (95% CI: ...

7. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2778657

Efficacy and Safety of First-line Single-Agent Carboplatin ... This randomized clinical trial compares the feasibility, efficacy, and safety of single-agent carboplatin every 3 weeks, ...