Phase II Trial of Transoral Surgical Resection Followed by De-escalated Adjuvant IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 150
- 试验地点
- 2
- 主要终点
- Recurrence-Free Survival (RFS)
研究概览
简要总结
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.
详细描述
This phase II trial is designed to rationally de-escalate adjuvant (Intensity Modulated Radiotherapy (IMRT) in the post-transoral surgery (TOS) setting in a study population consisting of patients with resectable oropharynx carcinoma, p16+ as confirmed by immunohistochemistry IHC, with a performance status (PS) of 0-1. Patients will be classified into one of three category/treatment groups (low-, intermediate-, and high-risk) according to their highest pathologically risk feature. Radiation will be given via an IMRT technique. For the high-risk patient group, a reduced, but slightly accelerated radiotherapy (RT) fractionation regimen of 50 Gy (HCC 18-034) in conjunction with cisplatin will be used compared to the standard 66 Gy and cisplatin. Low risk patients will transition to observation, intermediate risk patients will receive 30 Gy in 15 fractions of IMRT, and high risk patients will receive 50 Gy in 25 fractions (one day a week will include two treatments) plus 40 mg/m2 Cisplatin for 5 weeks. Patients who are not able to tolerate cisplatin will receive carboplatin instead.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •ECOG performance status of 0 or 1 or Karnofsky score 80-
- •Preference is to register patients prior to surgery. However, if not registered prior to surgery, the patient can be registered prior to adjuvant therapy.
- •Patients must have newly diagnosed, histologically or cytologically confirmed SCC or undifferentiated carcinoma of the oropharynx. Patients must have been determined to have resectable oropharyngeal disease. Patients with primary tumor or nodal metastasis fixed to the carotid artery, skull base or cervical spine are not eligible.
- •Patients must be deemed eligible for a TOS procedure with no evidence of distant metastasis as determined by imaging studies. Metastatic disease may be evaluated using CT or PET/CT where appropriate; this can be performed with or without contrast. The following imaging is acceptable to evaluate the primary and regional disease:
- •CT Neck (with contrast preferred but not required)
- •MRI Neck (contrast preferred but not required)
- •Patients must have biopsy-proven p16+ oropharynx cancer; the histologic evidence of invasive squamous cell carcinoma may have been obtained from the primary tumor or metastatic lymph node. It is required that patients have a positive p16 IHC (as surrogate for HPV) status from either the primary tumor or metastatic lymph node.
- •Carcinoma of the oropharynx associated with HPV as determined by p16 protein expression using immunohistochemistry (IHC) performed by a CLIA approved laboratory. Using p16 antibody obtained from Roche mtm laboratories AG (CINtec, clone E6H4) is recommended.
- •No prior radiation above the clavicles.
- •Patients with a history of a curatively treated malignancy must be disease-free for at least two years except for carcinoma in situ of cervix, melanoma in-situ (if fully resected), and/or non- melanomatous skin cancer.
- •Patients with the following within the last 6 months prior to registration must be evaluated by a cardiologist and/or neurologist prior to entry into the study.
- •Congestive heart failure > NYHA Class II
- •Unstable angina
- •Myocardial infarction (with or without ST elevation)
- •Patients must have acceptable renal and hepatic function within 4 weeks prior to registration
- •o For patients stratified following surgery and to concurrent chemotherapy (Arm CRT), calculated creatinine clearance must be > 60 ml/min using the Cockcroft-Gault formula
- •In patients with a contraindication to cisplatin, carboplatin can be used at time of patient enrollment if they are allocated to ARM CRT.
排除标准
- •No evidence of extensive or "matted/fixed" pathologic adenopathy on preoperative imaging.
- •Patients must not need a microvascular (free flap) reconstruction. Women must not be pregnant or breast-feeding due to the teratogenicity of chemotherapy. All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
- •Patient must not have an intercurrent illness likely to interfere with protocol therapy or prevent surgical resection
- •Patients must not have uncontrolled diabetes, uncontrolled infection despite antibiotics, or uncontrolled hypertension within 30 days prior to registration.
研究组 & 干预措施
Arm RT (Intermediate Risk)
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.
干预措施: laboratory biomarker analysis (Other)
Arm RT (Intermediate Risk)
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.
干预措施: quality-of-life assessment (Other)
Arm RT (Intermediate Risk)
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.
干预措施: intensity-modulated radiation therapy (Radiation)
Arm CRT (High Risk)
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)
干预措施: laboratory biomarker analysis (Other)
Arm CRT (High Risk)
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)
干预措施: quality-of-life assessment (Other)
Arm CRT (High Risk)
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)
干预措施: Carboplatin (Drug)
Arm CRT (High Risk)
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)
干预措施: Cisplatin (Drug)
Arm S (Low Risk)
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.
干预措施: therapeutic conventional surgery (Procedure)
Arm S (Low Risk)
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.
干预措施: laboratory biomarker analysis (Other)
Arm S (Low Risk)
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.
干预措施: quality-of-life assessment (Other)
Arm RT (Intermediate Risk)
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.
干预措施: therapeutic conventional surgery (Procedure)
Arm CRT (High Risk)
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)
干预措施: therapeutic conventional surgery (Procedure)
Arm CRT (High Risk)
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)
干预措施: intensity-modulated radiation therapy (Radiation)
结局指标
主要结局
Recurrence-Free Survival (RFS)
时间窗: Up to 2 years (for cohort)
Time to recurrence, defined as local and/or regional progression (identification of disease growth that is present within the area in which it was first located) and/or distant metastasis (identification of disease growth that is present in area(s) distant to that previously located). Local progression is defined as progression at the primary tumor site. Regional progression is defined as progression in the draining lymphatics (typically the cervical, retropharyngeal/retrostyloid and supraclavicular lymph nodes). Distant progression is defined as tumor recurrence in one or more non-local and non-regional sites (e.g., bone, lung, liver, etc.). Recurrent malignancy will be determined based on clinical exam and imaging findings. Patients who are disease-free but who die from other causes will be censored.
次要结局
- Loco-regional control (at 2 years)(Up to 2 year)
- Overall survival at 2 years(Up to 2 years)
- Quality of Life via FACT-HN(Baseline (before treatment), at 4-8 weeks post-surgery, at 3 months, 6 months, 1 year, up to 2 years following treatment)
- Modified Barium Swallow (MBS) rating(Before treatment, at 4-8 weeks post-surgery, 6 months and 24 months following treatment)
- MD Anderson Dysphagia Inventory (MDADI)(Baseline (before treatment), at 4-8 weeks post-surgery, at 1 year, up to 2 years following treatment)
- Loco-regional control (at 1 year)(Up to 1 year)
- Time to distant metastasis (at 1 year)(Up to 1 year)
- Overall survival at 1 year(Up to 1 year)
- Time to distant metastasis (at 2 years)(Up to 2 years)
- Adverse Events Related to Treatment(Up to 5 years)
- Voice outcomes(Baseline (before treatment), at 4-8 weeks post-surgery, at 1 year, up to 2 years following treatment)
- Performance Status Scale (PSS-HN)(Baseline (before treatment), at 4-8 weeks post-surgery, at 3 months, 6 months, 1 year, up to 2 years following treatment)
- Distribution of patients based on histologic risk features(Up to 3 years)
- Assessment of PEG tube dependence(At 1 year (post treatment))
- MD Anderson Symptom Inventory-Head & Neck (MDASI-HN)(Baseline (before treatment), at 4-8 weeks post-surgery, at 3 months, 6 months, up to 2 years following treatment)
研究者
Heath Skinner
Assistant Professor of Medicine
University of Pittsburgh