Adjuvant Therapy for HPV-Positive Oropharyngeal Cancer

(PATHOS Trial)

Not currently recruiting at 63 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Lisette Nixon

Disqualifiers: HPV negative, T4 tumors, N2c-N3 disease, current smokers, 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)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 6

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores ways to improve swallowing function and overall survival for individuals with HPV-positive oropharyngeal cancer, a type of throat cancer linked to the human papillomavirus. Researchers aim to determine if reducing the intensity of follow-up treatments, such as chemotherapy and radiotherapy, can still effectively control cancer while minimizing side effects. Participants will join different groups to compare the effects of no adjuvant treatment, radiotherapy alone, or radiotherapy combined with chemotherapy using the drug Cisplatin. This trial may suit individuals diagnosed with HPV-positive throat cancer who have undergone surgery. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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

The trial protocol 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.

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

Research has shown that radiation therapy after surgery is generally well-tolerated by patients with HPV-positive oropharyngeal cancer. One study found similar survival rates whether patients had surgery alone or with added radiation, indicating manageable side effects. Another study found a slight improvement in survival rates over three years for those who received radiation, with minimal extra risk.

Adding cisplatin, a chemotherapy drug, to radiation therapy proves effective but can cause side effects. A retrospective study reported that most patients who underwent this combination treatment experienced some side effects. However, most patients completed their treatment as planned, suggesting that while side effects occur, they are often manageable.

In summary, both treatments are relatively safe, with usually manageable side effects. Participants considering these treatments should weigh the benefits against potential side effects and discuss them with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the adjuvant therapies for HPV-positive oropharyngeal cancer because they explore various combinations of postoperative radiotherapy (PORT) with or without cisplatin chemotherapy. Unlike the standard care, which often involves a one-size-fits-all approach, these treatments are tailored to different risk levels. For instance, some patients receive lower doses of radiotherapy to minimize side effects, while others with high-risk features receive combined therapy with cisplatin, enhancing the treatment's effectiveness against aggressive cancer types. This personalized approach aims to improve outcomes while potentially reducing unnecessary treatment burdens on patients.

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

Studies have shown that radiation therapy after surgery can effectively treat HPV-positive throat cancer. Research indicates that this cancer type often responds well to radiation, significantly reducing the risk of death for patients receiving this treatment. In this trial, some participants will receive postoperative radiotherapy alone, while others will receive it with the drug cisplatin. Adding cisplatin to radiation therapy has shown even better results, improving survival rates. Specifically, studies found that patients treated with both radiation and cisplatin have better survival rates than those who received radiation with other drugs. This suggests that combining cisplatin with radiation therapy is a promising approach for treating HPV-positive throat cancer. ^{2 4 6 7 8}

Who Is on the Research Team?

Terrence Jones, MBBS,MD

Principal Investigator

Aintree University Hospital

Mererid Evans, MBBch, PhD

Principal Investigator

Velindre NHS Trust

Are You a Good Fit for This Trial?

The PATHOS trial is for adults over 18 with HPV-positive oropharyngeal cancer, who are fit for surgery and postoperative radiotherapy. It's not for those with HPV-negative tumors, distant metastatic disease, a recent history of other cancers (except certain skin/cervix cancers), pregnant/breastfeeding women not using contraception, or anyone with pre-existing conditions affecting swallowing.

Inclusion Criteria

Written informed consent provided

My throat cancer is suspected or confirmed to be squamous cell.

My cancer is at an early to mid-stage, not spread widely.

Exclusion Criteria

My head or neck cancer is not caused by HPV.

My tumor cannot be removed through surgery in the mouth.

My cancer has spread to distant parts of my body, confirmed by scans.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Surgery

Participants undergo transoral surgery for HPV-positive oropharyngeal cancer

1 week

1 visit (in-person)

Adjuvant Treatment

Participants receive postoperative radiotherapy with or without chemotherapy based on risk stratification

5-6 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety, effectiveness, and swallowing function post-treatment

24 months

Visits at 4 weeks, 6 months, 12 months, and 24 months post-treatment

What Are the Treatments Tested in This Trial?

Interventions

• Cisplatin
• Postoperative radiotherapy

Trial Overview This study tests if reducing the intensity of adjuvant treatments like Cisplatin and radiotherapy after transoral resection improves swallowing function in patients with HPV-positive oropharyngeal cancer without compromising overall survival.

How Is the Trial Designed?

Group I: C2: Postoperative radiotherapy 60 Gray without chemotherapy Experimental Treatment 1 Intervention

Arm C2: Postoperative radiotherapy at a dose of 60 Gray in 30 fractions over 6 weeks without chemotherapy (Test Arm C2). Group C: Patients with tumours of any T or any N stage, which exhibit the following high risk pathological features will be included: A histologically normal tissue margin around the primary tumour of \<1mm and, in the case of TLM, marginal biopsies free of tumour and /or extracapsular spread (ECS) of nodal disease

Group II: B2: Postoperative radiotherapy 50 Gray Experimental Treatment 1 Intervention

Arm B2: Postoperative radiotherapy (PORT) at a dose 50 Gray in 25 fractions over 5 weeks. Group B: Patients with: T3 tumours (or T1-T2 tumours with additional risk factors), TNM 7th edition pN2a (metastasis in single ipsilateral node 31-60 mm diameter) or pN2b (metastasis in multiple ipsilateral nodes \<61 mm diameter) disease, tumours with evidence of perineural and/or vascular invasion, and/or a histologically normal tissue margin around the primary tumour of 1-5mm and, in the case of TLM, marginal biopsies free of tumour.

Group III: A: No adjuvant treatment Active Control 1 Intervention

Group A Patients with tumours which exhibit no adverse histological features. Patients in this group will not receive any adjuvant treatment as per standard of care.

Group IV: B1: Postoperative radiotherapy 60 Gray Active Control 1 Intervention

Arm B1: postoperative radiotherapy (PORT) at a dose of 60 Gray (Gy) in 30 fractions over 6 weeks. Group B: Patients with: T3 tumours (or T1-T2 tumours with additional risk factors), TNM 7th edition pN2a (metastasis in single ipsilateral node 31-60 mm diameter) or pN2b (metastasis in multiple ipsilateral nodes \<61 mm diameter) disease, tumours with evidence of perineural and/or vascular invasion, and/or a histologically normal tissue margin around the primary tumour of 1-5mm and, in the case of TLM, marginal biopsies free of tumour.

Group V: C1: Postoperative radiotherapy 60 Gray with Cisplatin Active Control 2 Interventions

Arm C1: postoperative radiotherapy at a dose of 60 Gray in 30 fractions over 6 weeks with concurrent Cisplatin chemotherapy (POCRT). Cisplatin may be given 3 weekly (100mg/m2 week 1 and week 4 of radiotherapy) or weekly (40mg/m2 weekly during radiotherapy), according to local practice. Group C: Patients with tumours of any T or any N stage, which exhibit the following high risk pathological features will be included: A histologically normal tissue margin around the primary tumour of \<1mm and, in the case of TLM, marginal biopsies free of tumour and /or extracapsular spread (ECS) of nodal disease

Who Is Running the Clinical Trial?

Lisette Nixon

Lead Sponsor

Trials

6

Recruited

2,300+

UNICANCER

Collaborator

Trials

237

Recruited

352,000+

AdventHealth

Collaborator

Trials

118

Recruited

31,800+

Stanford University

Collaborator

Trials

2,527

Recruited

17,430,000+

Princess Alexandra Hospital, Brisbane, Australia

Collaborator

Trials

23

Recruited

26,900+

University of Leipzig

Collaborator

Trials

219

Recruited

1,288,000+

Published Research Related to This Trial

Patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) and nonsmokers showed better overall and disease-free survival, regardless of whether they received high dose (HD) or low dose (LD) cisplatin, indicating the importance of tumor characteristics in treatment outcomes.

A cumulative cisplatin dose of ≥200 mg/m2 was linked to a lower rate of distant metastasis, with the HD regimen allowing more patients to reach this dose while maintaining a similar toxicity profile to the LD regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deployment of cisplatin in Veterans with oropharyngeal cancer: toxicity and impact on oncologic outcomes. Soliman, O., Wilde, DC., Kemnade, JO., et al.[2023]

Patients with locally advanced oropharyngeal squamous cell carcinoma who received cisplatin (CDDP) had a significantly better 2-year overall survival rate compared to those treated with cetuximab (CTX), with a hazard ratio of 1.68 indicating higher mortality for CTX users.

Cisplatin also resulted in lower overall treatment costs compared to CTX and carboplatin, despite higher rates of antiemetic use and hospital visits for side effects, suggesting it may be a more cost-effective option for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing outcomes of concurrent chemotherapy regimens in patients 65 years old or older with locally advanced oropharyngeal carcinoma. Amini, A., Eguchi, M., Jones, BL., et al.[2023]

HPV-positive oral and oropharyngeal cancers have distinct molecular characteristics compared to HPV-negative cancers, leading to the need for tailored treatment regimens.

In HPV-positive cancers, drugs like pemetrexed and etoposide, which target thymidylate synthase and topoisomerase II, show greater efficacy than the standard cisplatin, suggesting they could be effective alternatives in treatment plans, although further clinical trials are necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of pemetrexed and etoposide as therapeutic regimens for human papillomavirus-positive oral and oropharyngeal cancer. Kim, YR., Lee, B., Byun, MR., et al.[2019]

In a phase 3 trial involving 334 patients with HPV-positive low-risk oropharyngeal cancer, cetuximab did not reduce severe toxicity compared to cisplatin, with both treatments showing similar rates of severe side effects at 24 months.

However, cetuximab was associated with significantly worse outcomes in terms of overall survival (89.4% vs 97.5%) and recurrence rates (16.1% vs 6.0%) compared to cisplatin, indicating that cisplatin remains the preferred treatment for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. Mehanna, H., Robinson, M., Hartley, A., et al.[2023]

In the De-ESCALaTE HPV trial involving 334 patients, cisplatin demonstrated superior overall survival (97.5% vs 90.0%) and lower recurrence rates (6.4% vs 16.0%) compared to cetuximab for treating HPV-positive oropharyngeal squamous cell carcinoma.

Cisplatin not only provided more quality-adjusted life years (QALYs) but was also significantly less expensive than cetuximab, with average costs of £13,517 for cisplatin versus £21,064 for cetuximab, making cisplatin the preferred treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent cisplatin or cetuximab with radiotherapy for HPV-positive oropharyngeal cancer: Medical resource use, costs, and quality-adjusted survival from the De-ESCALaTE HPV trial. Jones, DA., Mistry, P., Dalby, M., et al.[2021]

In a meta-analysis of 8 studies involving 1665 patients, treatment with cisplatin (CDDP) combined with radiotherapy resulted in significantly better overall survival (OS) and lower rates of locoregional recurrence (LRR) compared to cetuximab (C225) with radiotherapy for HPV-positive oropharyngeal cancer.

Patients receiving CDDP had a 2.2-fold lower risk of death and a 2.9-fold lower risk of locoregional recurrence, indicating that CDDP-based chemoradiotherapy should remain the standard treatment for p16-positive oropharyngeal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin-based chemoradiotherapy vs. cetuximab-based bioradiotherapy for p16-positive oropharyngeal cancer: an updated meta-analysis including trials RTOG 1016 and De-ESCALaTE. Suton, P., Skelin, M., Rakusic, Z., et al.[2020]

In a study of 160 patients with advanced oropharyngeal squamous cell carcinoma treated with carboplatin, paclitaxel, and radiation over 10 years, the overall survival rates were 81.7% at 3 years and 70.7% at 5 years, indicating effective treatment outcomes.

The treatment demonstrated an acceptable side effect profile, with the most common adverse effect being acute dysphagia (75.25%), and only 11.9% of patients experiencing significant hematologic toxicities, suggesting carboplatin may be a safer alternative to cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival outcomes in patients with oropharyngeal cancer treated with carboplatin/paclitaxel and concurrent radiotherapy. Roskies, M., Kay-Rivest, E., Mascarella, MA., et al.[2018]

HPV-associated oropharyngeal squamous cell carcinomas respond well to radiation and chemotherapy, leading to a generally favorable prognosis, which supports the exploration of treatment de-intensification strategies.

Transoral Robotic Surgery combined with reduced adjuvant therapy shows promise in minimizing treatment toxicity while maintaining effectiveness, and personalized approaches using tumor biology and imaging markers are helping to further tailor and reduce the intensity of radiotherapy and chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HPV-associated oropharyngeal cancer de-escalation strategies and trials: Past failures and future promise. Zakeri, K., Dunn, L., Lee, N.[2022]

In a study of 1,149 patients with advanced head and neck squamous cell carcinoma, carboplatin-based chemoradiotherapy showed similar cancer-specific mortality rates compared to cisplatin-based therapy, indicating that carboplatin can be an effective alternative for patients unable to receive cisplatin.

Both carboplatin and cisplatin-based chemoradiotherapy were found to be more effective than radiation therapy alone or radiation with cetuximab, suggesting that carboplatin should be further investigated as a viable treatment option for certain patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival After Definitive Chemoradiotherapy With Concurrent Cisplatin or Carboplatin for Head and Neck Cancer. Xiang, M., Colevas, AD., Holsinger, FC., et al.[2020]

In a study of 104 patients with locally advanced head and neck squamous cell carcinoma, there was no significant difference in overall survival or recurrence-free survival between those treated with high-dose cisplatin and those treated with weekly cisplatin after surgery and chemoradiation.

The results suggest that weekly cisplatin may be a preferable option for patients with HPV-positive oropharynx cancer, as it could help maintain survival rates while potentially reducing treatment-related toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant chemoradiation therapy with high-dose versus weekly cisplatin for resected, locally-advanced HPV/p16-positive and negative head and neck squamous cell carcinoma. Geiger, JL., Lazim, AF., Walsh, FJ., et al.[2022]

A phase 2 trial involving 39 patients with HPV-related oropharyngeal squamous cell carcinoma showed that intensity-modulated radiation therapy (IMRT) alone resulted in a 90% complete response rate, indicating high efficacy without chemotherapy.

The treatment demonstrated a 2-year progression-free survival rate of 94% and a 100% overall survival rate, with manageable toxicity, as only 26% experienced severe mucositis and no long-term severe adverse effects were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation Therapy Alone for Human Papillomavirus-Related Squamous Cell Carcinoma of the Oropharynx: A Single-Arm, Phase 2 Study. Takemoto, N., Seo, Y., Nakahara, S., et al.[2021]

In a study of 22 patients with HPV-negative oropharyngeal cancer, selective intraarterial chemoradiotherapy using docetaxel and nedaplatin resulted in a complete response in all patients after treatment, indicating high efficacy.

The 5-year survival rates were impressive, with 96% locoregional control, 91% disease-free survival, and 100% overall survival, suggesting that this treatment approach could be a promising option for this challenging cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic efficacy of selective intraarterial chemoradiotherapy with docetaxel and nedaplatin for human papilloma virus-negative oropharyngeal cancer. Heianna, J., Makino, W., Hirakawa, H., et al.[2022]

HPV-positive oropharyngeal tumors are approximately 5 times more radiosensitive than HPV-negative tumors, leading to better outcomes for patients with HPV-positive cancers when treated with radiation and chemotherapy.

Concurrent cisplatin chemotherapy significantly enhances the effectiveness of fractionated radiation therapy, resulting in a 26% higher survival rate in mice with HPV-positive tumors compared to those with HPV-negative tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic effect of cisplatin chemotherapy combined with fractionated radiotherapy regimen in HPV-positive and HPV-negative experimental pharyngeal squamous cell carcinoma. Kranjc Brezar, S., Prevc, A., Niksic Zakelj, M., et al.[2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40829719/

Self-Perceived Hearing Outcomes with Radiation and ... Patients have significantly worse self-perceived hearing handicap after receiving RT+Cis treatment than with RT+Cetux.

2. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(18)32752-1/fulltext

Radiotherapy plus cisplatin or cetuximab in low-risk human ... Meta-analyses of existing small, mainly retrospective studies reported poorer outcomes with cetuximab than with cisplatin for head and neck ...

3. frontiersin.org frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1175578/full

De-escalated radiation for human papillomavirus virus ... 65%) and overall survival (82% vs. 57%) between 433 patients with HPV-positive and HPV-negative phenotypes treated prospectively by cisplatin-based ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34311328/

The important role of cisplatin in the treatment of HPV ... This study using causal inference of retrospective patient data confirms the important role of cisplatin in the treatment of HPV-positive ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1368837521005595

The important role of cisplatin in the treatment of HPV ... Two randomized controlled trials (RCTs) reported inferior survival of HPV-positive OPSCC treated with radiotherapy plus cetuximab compared to standard of care ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11513364/

Retrospective study of cisplatin plus radiotherapy toxicities ... A total of 274 (84%) patients were compliant and received the planned dose of cisplatin. Overall, 957 adverse events were reported in 98.2% of ...

7. nature.com nature.com/articles/s44276-025-00164-z

Long-term outcomes of consecutive patients of ... HPV-positive cohort showed significantly better outcomes compared to HPV-negative cohort with 5-year LC, LRC, DFS, OS of 84.4% vs 43.5% (p < ...

8. practicalradonc.org practicalradonc.org/article/S1879-8500(24)00139-5/fulltext

Radiation Therapy for HPV-Positive Oropharyngeal ... Cervical nodal level V can safely be omitted in the treatment of locally advanced oropharyngeal squamous cell carcinoma with definitive IMRT.